Review Article | Published:

T cell-mediated immunity to malaria



Immunity to malaria has been linked to the availability and function of helper CD4+ T cells, cytotoxic CD8+ T cells and γδ T cells that can respond to both the asymptomatic liver stage and the symptomatic blood stage of Plasmodium sp. infection. These T cell responses are also thought to be modulated by regulatory T cells. However, the precise mechanisms governing the development and function of Plasmodium-specific T cells and their capacity to form tissue-resident and long-lived memory populations are less well understood. The field has arrived at a point where the push for vaccines that exploit T cell-mediated immunity to malaria has made it imperative to define and reconcile the mechanisms that regulate the development and functions of Plasmodium-specific T cells. Here, we review our current understanding of the mechanisms by which T cell subsets orchestrate host resistance to Plasmodium infection on the basis of observational and mechanistic studies in humans, non-human primates and rodent models. We also examine the potential of new experimental strategies and human infection systems to inform a new generation of approaches to harness T cell responses against malaria.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    World Health Organization. World Malaria Report 2018 (WHO, 2018).

  2. 2.

    Regules, J. A. et al. Fractional third and fourth dose of RTS,S/AS01 malaria candidate vaccine: a phase 2a controlled human malaria parasite infection and immunogenicity study. J. Infect. Dis. 214, 762–771 (2016).

  3. 3.

    RTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet 386, 31–45 (2015).

  4. 4.

    White, M. T. et al. Immunogenicity of the RTS,S/AS01 malaria vaccine and implications for duration of vaccine efficacy: secondary analysis of data from a phase 3 randomised controlled trial. Lancet Infect. Dis. 15, 1450–1458 (2015).

  5. 5.

    Ishizuka, A. S. et al. Protection against malaria at 1 year and immune correlates following PfSPZ vaccination. Nat. Med. 22, 614–623 (2016).

  6. 6.

    Mordmuller, B. et al. Sterile protection against human malaria by chemoattenuated PfSPZ vaccine. Nature 542, 445–449 (2017).

  7. 7.

    Roestenberg, M. et al. Protection against a malaria challenge by sporozoite inoculation. N. Engl. J. Med. 361, 468–477 (2009).

  8. 8.

    Seder, R. A. et al. Protection against malaria by intravenous immunization with a nonreplicating sporozoite vaccine. Science 341, 1359–1365 (2013). This study demonstrates that there is a dose-dependent immunological threshold for establishing protection against malaria that can be achieved with intravenous administration of a live-attenuated sporozoite vaccine.

  9. 9.

    Ewer, K. J. et al. Protective CD8+ T cell immunity to human malaria induced by chimpanzee adenovirus-MVA immunisation. Nat. Commun. 4, 2836 (2013).

  10. 10.

    Sissoko, M. S. et al. Safety and efficacy of PfSPZ vaccine against Plasmodium falciparum via direct venous inoculation in healthy malaria-exposed adults in Mali: a randomised, double-blind phase 1 trial. Lancet Infect. Dis. 17, 498–509 (2017).

  11. 11.

    Wykes, M. N. & Lewin, S. R. Immune checkpoint blockade in infectious diseases. Nat. Rev. Immunol. 18, 91–104 (2018).

  12. 12.

    Soon, M. S. F. & Haque, A. Recent insights into CD4(+) Th cell differentiation in malaria. J. Immunol. 200, 1965–1975 (2018).

  13. 13.

    Montes de Oca, M., Good, M. F., McCarthy, J. S. & Engwerda, C. R. The impact of established immunoregulatory networks on vaccine efficacy and the development of immunity to malaria. J. Immunol. 197, 4518–4526 (2016).

  14. 14.

    Troye-Blomberg, M. et al. Production of IL 2 and IFN-gamma by T cells from malaria patients in response to Plasmodium falciparum or erythrocyte antigens in vitro. J. Immunol. 135, 3498–3504 (1985).

  15. 15.

    Su, Z. & Stevenson, M. M. Central role of endogenous gamma interferon in protective immunity against blood-stage Plasmodium chabaudi AS infection. Infect. Immun. 68, 4399–4406 (2000).

  16. 16.

    Meding, S. J., Cheng, S. C., Simon-Haarhaus, B. & Langhorne, J. Role of gamma interferon during infection with Plasmodium chabaudi chabaudi. Infect. Immun. 58, 3671–3678 (1990).

  17. 17.

    Huang, K. Y., Schultz, W. W. & Gordon, F. B. Interferon induced by Plasmodium berghei. Science 162, 123–124 (1968).

  18. 18.

    Shear, H. L., Srinivasan, R., Nolan, T. & Ng, C. Role of IFN-gamma in lethal and nonlethal malaria in susceptible and resistant murine hosts. J. Immunol. 143, 2038–2044 (1989).

  19. 19.

    Salles, E. M. et al. P2X7 receptor drives Th1 cell differentiation and controls the follicular helper T cell population to protect against Plasmodium chabaudi malaria. PLOS Pathog. 13, e1006595 (2017).

  20. 20.

    Gotz, A. et al. Atypical activation of dendritic cells by Plasmodium falciparum. Proc. Natl Acad. Sci. USA 114, E10568–E10577 (2017).

  21. 21.

    Lazarevic, V., Glimcher, L. H. & Lord, G. M. T-bet: a bridge between innate and adaptive immunity. Nat. Rev. Immunol. 13, 777–789 (2013).

  22. 22.

    Oakley, M. S. et al. T-bet modulates the antibody response and immune protection during murine malaria. Eur. J. Immunol. 44, 2680–2691 (2014).

  23. 23.

    Riley, E. M. & Stewart, V. A. Immune mechanisms in malaria: new insights in vaccine development. Nat. Med. 19, 168–178 (2013).

  24. 24.

    Bastos, K. R. et al. Impaired macrophage responses may contribute to exacerbation of blood-stage Plasmodium chabaudi chabaudi malaria in interleukin-12-deficient mice. J. Interferon Cytokine Res. 22, 1191–1199 (2002).

  25. 25.

    Jaramillo, M., Gowda, D. C., Radzioch, D. & Olivier, M. Hemozoin increases IFN-gamma-inducible macrophage nitric oxide generation through extracellular signal-regulated kinase- and NF-kappa B-dependent pathways. J. Immunol. 171, 4243–4253 (2003).

  26. 26.

    Blanchette, J., Jaramillo, M. & Olivier, M. Signalling events involved in interferon-gamma-inducible macrophage nitric oxide generation. Immunology 108, 513–522 (2003).

  27. 27.

    Horowitz, A. et al. Cross-talk between T cells and NK cells generates rapid effector responses to Plasmodium falciparum-infected erythrocytes. J. Immunol. 184, 6043–6052 (2010).

  28. 28.

    Fontana, M. F. et al. Macrophage colony stimulating factor derived from CD4+ T cells contributes to control of a blood-borne infection. PLOS Pathog. 12, e1006046 (2016).

  29. 29.

    Weiss, W. R. et al. A plasmid encoding murine granulocyte-macrophage colony-stimulating factor increases protection conferred by a malaria DNA vaccine. J. Immunol. 161, 2325–2332 (1998).

  30. 30.

    Stephens, R. & Langhorne, J. Effector memory Th1 CD4 T cells are maintained in a mouse model of chronic malaria. PLOS Pathog. 6, e1001208 (2010).

  31. 31.

    Opata, M. M. et al. Early effector cells survive the contraction phase in malaria infection and generate both central and effector memory T cells. J. Immunol. 194, 5346–5354 (2015).

  32. 32.

    Opata, M. M. et al. Protection by and maintenance of CD4 effector memory and effector T cell subsets in persistent malaria infection. PLOS Pathog. 14, e1006960 (2018).

  33. 33.

    Zander, R. A. et al. Th1-like Plasmodium-specific memory CD4(+) T cells support humoral immunity. Cell Rep. 21, 1839–1852 (2017).

  34. 34.

    Reece, W. H. et al. A CD4(+) T cell immune response to a conserved epitope in the circumsporozoite protein correlates with protection from natural Plasmodium falciparum infection and disease. Nat. Med. 10, 406–410 (2004).

  35. 35.

    Oliveira, G. A. et al. Class II-restricted protective immunity induced by malaria sporozoites. Infect. Immun. 76, 1200–1206 (2008).

  36. 36.

    Renia, L. et al. Effector functions of circumsporozoite peptide-primed CD4+ T cell clones against Plasmodium yoelii liver stages. J. Immunol. 150, 1471–1478 (1993).

  37. 37.

    Doolan, D. L. et al. Circumventing genetic restriction of protection against malaria with multigene DNA immunization: CD8+ cell-, interferon gamma-, and nitric oxide-dependent immunity. J. Exp. Med. 183, 1739–1746 (1996).

  38. 38.

    Sun, P. et al. Protective immunity induced with malaria vaccine, RTS,S, is linked to Plasmodium falciparum circumsporozoite protein-specific CD4+ and CD8+ T cells producing IFN-gamma. J. Immunol. 171, 6961–6967 (2003).

  39. 39.

    Burel, J. G. et al. Reduced Plasmodium parasite burden associates with CD38+ CD4+ T cells displaying cytolytic potential and impaired IFN-gamma production. PLOS Pathog. 12, e1005839 (2016).

  40. 40.

    Bijker, E. M. et al. Cytotoxic markers associate with protection against malaria in human volunteers immunized with Plasmodium falciparum sporozoites. J. Infect. Dis. 210, 1605–1615 (2014).

  41. 41.

    Tsuji, M., Romero, P., Nussenzweig, R. S. & Zavala, F. CD4+ cytolytic T cell clone confers protection against murine malaria. J. Exp. Med. 172, 1353–1357 (1990). This study identifies a protective MHC class II-restricted antigen from Plasmodium in mice.

  42. 42.

    Takita-Sonoda, Y. et al. Plasmodium yoelii: peptide immunization induces protective CD4+ T cells against a previously unrecognized cryptic epitope of the circumsporozoite protein. Exp. Parasitol. 84, 223–230 (1996).

  43. 43.

    Obeng-Adjei, N. et al. Malaria-induced interferon-gamma drives the expansion of Tbethi atypical memory B cells. PLOS Pathog. 13, e1006576 (2017).

  44. 44.

    Zander, R. A. et al. PD-1 co-inhibitory and OX40 co-stimulatory crosstalk regulates helper T cell differentiation and anti-Plasmodium humoral immunity. Cell Host Microbe 17, 628–641 (2015).

  45. 45.

    Ryg-Cornejo, V. et al. Severe malaria infections impair germinal center responses by inhibiting T follicular helper cell differentiation. Cell Rep. 14, 68–81 (2016).

  46. 46.

    Guthmiller, J. J., Graham, A. C., Zander, R. A., Pope, R. L. & Butler, N. S. Cutting edge: IL-10 is essential for the generation of germinal center B cell responses and anti-Plasmodium humoral immunity. J. Immunol. 198, 617–622 (2017).

  47. 47.

    Rivera-Correa, J. et al. Plasmodium DNA-mediated TLR9 activation of T-bet(+) B cells contributes to autoimmune anaemia during malaria. Nat. Commun. 8, 1282 (2017).

  48. 48.

    Walker, J. A. & McKenzie, A. N. J. TH2 cell development and function. Nat. Rev. Immunol. 18, 121–133 (2018).

  49. 49.

    Perez-Mazliah, D. & Langhorne, J. CD4 T cell subsets in malaria: TH1/TH2 revisited. Front. Immunol. 5, 671 (2014).

  50. 50.

    Coomes, S. M. et al. IFNgamma and IL-12 restrict Th2 responses during Helminth/Plasmodium co-infection and promote IFNgamma from Th2 cells. PLOS Pathog. 11, e1004994 (2015).

  51. 51.

    Shimoda, K. et al. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 380, 630–633 (1996).

  52. 52.

    von der Weid, T., Kopf, M., Kohler, G. & Langhorne, J. The immune response to Plasmodium chabaudi malaria in interleukin-4-deficient mice. Eur. J. Immunol. 24, 2285–2293 (1994).

  53. 53.

    Kumaratilake, L. M. & Ferrante, A. IL-4 inhibits macrophage-mediated killing of Plasmodium falciparum in vitro. A possible parasite-immune evasion mechanism. J. Immunol. 149, 194–199 (1992).

  54. 54.

    Troye-Blomberg, M. et al. Production by activated human T cells of interleukin 4 but not interferon-gamma is associated with elevated levels of serum antibodies to activating malaria antigens. Proc. Natl Acad. Sci. USA 87, 5484–5488 (1990).

  55. 55.

    Carvalho, L. H. et al. IL-4-secreting CD4+ T cells are crucial to the development of CD8+ T cell responses against malaria liver stages. Nat. Med. 8, 166–170 (2002). This work demonstrates the mechanism of CD4 + T cell help in the development of optimal CD8 + T cell responses to liver-stage malaria.

  56. 56.

    Overstreet, M. G., Chen, Y. C., Cockburn, I. A., Tse, S. W. & Zavala, F. CD4+ T cells modulate expansion and survival but not functional properties of effector and memory CD8+ T cells induced by malaria sporozoites. PLOS ONE 6, e15948 (2011).

  57. 57.

    Vinuesa, C. G. & Cyster, J. G. How T cells earn the follicular rite of passage. Immunity 35, 671–680 (2011).

  58. 58.

    Victora, G. D. & Nussenzweig, M. C. Germinal centers. Annu. Rev. Immunol. 30, 429–457 (2012).

  59. 59.

    Obeng-Adjei, N. et al. Circulating Th1-cell-type Tfh cells that exhibit impaired B cell help are preferentially activated during acute malaria in children. Cell Rep. 13, 425–439 (2015). This study suggests that the circulating PD1 + CXCR5 + CXCR3 T FH cells provide B cell help that facilitates long-lived antibody-mediated protection in humans.

  60. 60.

    Butler, N. S. et al. Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection. Nat. Immunol. 13, 188–195 (2012). This study shows that blood-stage malaria may be associated with T cell dysfunction that is linked to T cell expression of inhibitory receptors.

  61. 61.

    Perez-Mazliah, D. et al. Follicular helper T cells are essential for the elimination of Plasmodium infection. EBioMedicine 24, 216–230 (2017).

  62. 62.

    Figueiredo, M. M. et al. T follicular helper cells regulate the activation of B lymphocytes and antibody production during Plasmodium vivax infection. PLOS Pathog. 13, e1006484 (2017).

  63. 63.

    Perez-Mazliah, D. et al. Disruption of IL-21 signaling affects T cell-B cell interactions and abrogates protective humoral immunity to malaria. PLOS Pathog. 11, e1004715 (2015).

  64. 64.

    Sebina, I. et al. IFNAR1-signalling obstructs ICOS-mediated humoral immunity during non-lethal blood-stage Plasmodium infection. PLOS Pathog. 12, e1005999 (2016).

  65. 65.

    Wikenheiser, D. J., Ghosh, D., Kennedy, B. & Stumhofer, J. S. The costimulatory molecule ICOS regulates host Th1 and follicular Th cell differentiation in response to Plasmodium chabaudi chabaudi AS infection. J. Immunol. 196, 778–791 (2016).

  66. 66.

    Hale, J. S. et al. Distinct memory CD4+ T cells with commitment to T follicular helper- and T helper 1-cell lineages are generated after acute viral infection. Immunity 38, 805–817 (2013).

  67. 67.

    Pepper, M., Pagan, A. J., Igyarto, B. Z., Taylor, J. J. & Jenkins, M. K. Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells. Immunity 35, 583–595 (2011).

  68. 68.

    Lonnberg, T. S. et al. Single-cell RNA-seq and computational analysis using temporal micture modeling resolves TH1/TFH fate bifurcation in malaria. Sci. Immunol. 2, eaal2192 (2017).

  69. 69.

    Sebina, I. et al. IL-6 promotes CD4(+) T cell and B cell activation during Plasmodium infection. Parasite Immunol. 39, e12455 (2017).

  70. 70.

    James, K. R. et al. IFN regulatory factor 3 balances Th1 and T follicular helper immunity during nonlethal blood-stage Plasmodium infection. J. Immunol. 200, 1443–1456 (2018).

  71. 71.

    Wikenheiser, D. J., Brown, S. L., Lee, J. & Stumhofer, J. S. NK1.1 expression defines a population of CD4(+) effector T cells displaying Th1 and Tfh cell properties that support early antibody production during Plasmodium yoelii infection. Front. Immunol. 9, 2277 (2018).

  72. 72.

    Troye-Blomberg, M. et al. Human gamma delta T cells that inhibit the in vitro growth of the asexual blood stages of the Plasmodium falciparum parasite express cytolytic and proinflammatory molecules. Scand. J. Immunol. 50, 642–650 (1999).

  73. 73.

    Kurup, S. P. et al. Regulatory T cells impede acute and long-term immunity to blood-stage malaria through CTLA-4. Nat. Med. 23, 1220–1225 (2017). This study demonstrates a temporal role and mechanism of regulatory T cell function in blood-stage malaria.

  74. 74.

    Sage, P. T. & Sharpe, A. H. T follicular regulatory cells. Immunol. Rev. 271, 246–259 (2016).

  75. 75.

    Laidlaw, B. J. et al. Interleukin-10 from CD4(+) follicular regulatory T cells promotes the germinal center response. Sci. Immunol. 2, eaan4767 (2017).

  76. 76.

    Wing, J. B., Tekguc, M. & Sakaguchi, S. Control of germinal center responses by T-follicular regulatory cells. Front. Immunol. 9, 1910 (2018).

  77. 77.

    Xie, M. M. & Dent, A. L. Unexpected help: follicular regulatory T cells in the germinal center. Front. Immunol. 9, 1536 (2018).

  78. 78.

    Sandquist, I. & Kolls, J. Update on regulation and effector functions of Th17 cells. F1000Res 7, 205 (2018).

  79. 79.

    Sercundes, M. K. et al. Targeting neutrophils to prevent malaria-associated acute lung injury/acute respiratory distress syndrome in mice. PLOS Pathog. 12, e1006054 (2016).

  80. 80.

    Feintuch, C. M. et al. Activated neutrophils are associated with pediatric cerebral malaria vasculopathy in malawian children. MBio 7, e01300–15 (2016).

  81. 81.

    Metenou, S. et al. Filarial infection suppresses malaria-specific multifunctional Th1 and Th17 responses in malaria and filarial coinfections. J. Immunol. 186, 4725–4733 (2011).

  82. 82.

    Ishida, H. et al. Development of experimental cerebral malaria is independent of IL-23 and IL-17. Biochem. Biophys. Res. Commun. 402, 790–795 (2010).

  83. 83.

    Mastelic, B. et al. IL-22 protects against liver pathology and lethality of an experimental blood-stage malaria infection. Front. Immunol. 3, 85 (2012).

  84. 84.

    Keswani, T. & Bhattacharyya, A. Differential role of T regulatory and Th17 in Swiss mice infected with Plasmodium berghei ANKA and Plasmodium yoelii. Exp. Parasitol. 141, 82–92 (2014).

  85. 85.

    Hu, W. C. Human immune responses to Plasmodium falciparum infection: molecular evidence for a suboptimal THalphabeta and TH17 bias over ideal and effective traditional TH1 immune response. Malar J. 12, 392 (2013).

  86. 86.

    Wei, L., Laurence, A., Elias, K. M. & O’Shea, J. J. IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. J. Biol. Chem. 282, 34605–34610 (2007).

  87. 87.

    Moretto, M. M., Hwang, S. & Khan, I. A. Downregulated IL-21 response and T follicular helper cell exhaustion correlate with compromised CD8 T cell immunity during chronic toxoplasmosis. Front. Immunol. 8, 1436 (2017).

  88. 88.

    Stumhofer, J. S., Silver, J. S. & Hunter, C. A. IL-21 is required for optimal antibody production and T cell responses during chronic Toxoplasma gondii infection. PLOS ONE 8, e62889 (2013).

  89. 89.

    Findlay, E. G. et al. Essential role for IL-27 receptor signaling in prevention of Th1-mediated immunopathology during malaria infection. J. Immunol. 185, 2482–2492 (2010).

  90. 90.

    Freitas do Rosario, A. P. et al. IL-27 promotes IL-10 production by effector Th1 CD4+ T cells: a critical mechanism for protection from severe immunopathology during malaria infection. J. Immunol. 188, 1178–1190 (2012).

  91. 91.

    Gwyer Findlay, E. et al. IL-27 receptor signaling regulates memory CD4+ T cell populations and suppresses rapid inflammatory responses during secondary malaria infection. Infect. Immun. 82, 10–20 (2014).

  92. 92.

    Kimura, D. et al. Interleukin-27-producing CD4(+) T cells regulate protective immunity during malaria parasite infection. Immunity 44, 672–682 (2016).

  93. 93.

    Couper, K. N. et al. IL-10 from CD4+CD25Foxp3CD127 adaptive regulatory T cells modulates parasite clearance and pathology during malaria infection. PLOS Pathog. 4, e1000004 (2008).

  94. 94.

    Zander, R. A. et al. Type I interferons induce T regulatory 1 responses and restrict humoral immunity during experimental malaria. PLOS Pathog. 12, e1005945 (2016).

  95. 95.

    Jagannathan, P. et al. IFNgamma/IL-10 co-producing cells dominate the CD4 response to malaria in highly exposed children. PLOS Pathog. 10, e1003864 (2014).

  96. 96.

    Loevenich, K. et al. DC-derived IL-10 modulates pro-inflammatory cytokine production and promotes induction of CD4(+)IL-10(+) regulatory T cells during Plasmodium yoelii infection. Front. Immunol. 8, 152 (2017).

  97. 97.

    Draheim, M. et al. Profiling MHC II immunopeptidome of blood-stage malaria reveals that cDC1 control the functionality of parasite-specific CD4 T cells. EMBO Mol. Med. 9, 1605–1621 (2017).

  98. 98.

    Montes de Oca, M. et al. Type I interferons regulate immune responses in humans with blood-stage Plasmodium falciparum infection. Cell Rep. 17, 399–412 (2016).

  99. 99.

    Jankovic, D. et al. Conventional T-bet(+)Foxp3(-) Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection. J. Exp. Med. 204, 273–283 (2007).

  100. 100.

    Montes de Oca, M. et al. Blimp-1-dependent IL-10 production by Tr1 cells regulates TNF-mediated tissue pathology. PLOS Pathog. 12, e1005398 (2016).

  101. 101.

    Walther, M. et al. Distinct roles for FOXP3 and FOXP3 CD4 T cells in regulating cellular immunity to uncomplicated and severe Plasmodium falciparum malaria. PLOS Pathog. 5, e1000364 (2009).

  102. 102.

    Boyle, M. J. et al. The development of Plasmodium falciparum-specific IL10 CD4 T cells and protection from malaria in children in an area of high malaria transmission. Front. Immunol. 8, 1329 (2017).

  103. 103.

    Miyao, T. et al. Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 36, 262–275 (2012).

  104. 104.

    Ohkura, N. et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 37, 785–799 (2012).

  105. 105.

    Yadav, M., Stephan, S. & Bluestone, J. A. Peripherally induced tregs - role in immune homeostasis and autoimmunity. Front. Immunol. 4, 232 (2013).

  106. 106.

    Van Braeckel-Budimir, N., Kurup, S. P. & Harty, J. T. Regulatory issues in immunity to liver and blood-stage malaria. Curr. Opin. Immunol. 42, 91–97 (2016).

  107. 107.

    Finney, O. C., Riley, E. M. & Walther, M. Regulatory T cells in malaria—friend or foe? Trends Immunol. 31, 63–70 (2010).

  108. 108.

    Hansen, D. S. & Schofield, L. Natural regulatory T cells in malaria: host or parasite allies? PLOS Pathog. 6, e1000771 (2010).

  109. 109.

    Couper, K. N. et al. Incomplete depletion and rapid regeneration of Foxp3+ regulatory T cells following anti-CD25 treatment in malaria-infected mice. J. Immunol. 178, 4136–4146 (2007).

  110. 110.

    Hisaeda, H. et al. Escape of malaria parasites from host immunity requires CD4+ CD25+ regulatory T cells. Nat. Med. 10, 29–30 (2004). This work shows that T reg cells may be detrimental to the optimal control of blood-stage malaria using a mouse model.

  111. 111.

    Cambos, M., Belanger, B., Jacques, A., Roulet, A. & Scorza, T. Natural regulatory (CD4+CD25+FOXP+) T cells control the production of pro-inflammatory cytokines during Plasmodium chabaudi adami infection and do not contribute to immune evasion. Int. J. Parasitol. 38, 229–238 (2008).

  112. 112.

    Feuerer, M., Shen, Y., Littman, D. R., Benoist, C. & Mathis, D. How punctual ablation of regulatory T cells unleashes an autoimmune lesion within the pancreatic islets. Immunity 31, 654–664 (2009).

  113. 113.

    Kim, J. M., Rasmussen, J. P. & Rudensky, A. Y. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8, 191–197 (2007).

  114. 114.

    Vigario, A. M. et al. Regulatory CD4+ CD25+ Foxp3+ T cells expand during experimental Plasmodium infection but do not prevent cerebral malaria. Int. J. Parasitol. 37, 963–973 (2007).

  115. 115.

    Amante, F. H. et al. A role for natural regulatory T cells in the pathogenesis of experimental cerebral malaria. Am. J. Pathol. 171, 548–559 (2007).

  116. 116.

    Steeg, C., Adler, G., Sparwasser, T., Fleischer, B. & Jacobs, T. Limited role of CD4+Foxp3+ regulatory T cells in the control of experimental cerebral malaria. J. Immunol. 183, 7014–7022 (2009).

  117. 117.

    Jangpatarapongsa, K. et al. Plasmodium vivax parasites alter the balance of myeloid and plasmacytoid dendritic cells and the induction of regulatory T cells. Eur. J. Immunol. 38, 2697–2705 (2008).

  118. 118.

    Torcia, M. G. et al. Functional deficit of T regulatory cells in Fulani, an ethnic group with low susceptibility to Plasmodium falciparum malaria. Proc. Natl Acad. Sci. USA 105, 646–651 (2008).

  119. 119.

    Walther, M. et al. Upregulation of TGF-beta, FOXP3, and CD4+CD25+ regulatory T cells correlates with more rapid parasite growth in human malaria infection. Immunity 23, 287–296 (2005). This study demonstrates that T reg cell expansions during blood-stage malaria in humans correlate with poor control of the infection.

  120. 120.

    Todryk, S. M. et al. Correlation of memory T cell responses against TRAP with protection from clinical malaria, and CD4 CD25 high T cells with susceptibility in Kenyans. PLOS ONE 3, e2027 (2008).

  121. 121.

    Apostolou, I. & von Boehmer, H. In vivo instruction of suppressor commitment in naive T cells. J. Exp. Med. 199, 1401–1408 (2004).

  122. 122.

    Benoist, C. & Mathis, D. Treg cells, life history, and diversity. Cold Spring Harb. Perspect. Biol. 4, a007021 (2012).

  123. 123.

    Finney, C. A., Taylor, M. D., Wilson, M. S. & Maizels, R. M. Expansion and activation of CD4(+)CD25(+) regulatory T cells in Heligmosomoides polygyrus infection. Eur. J. Immunol. 37, 1874–1886 (2007).

  124. 124.

    Haribhai, D. et al. A central role for induced regulatory T cells in tolerance induction in experimental colitis. J. Immunol. 182, 3461–3468 (2009).

  125. 125.

    Haribhai, D. et al. A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity. Immunity 35, 109–122 (2011).

  126. 126.

    Lathrop, S. K. et al. Peripheral education of the immune system by colonic commensal microbiota. Nature 478, 250–254 (2011).

  127. 127.

    Elkord, E. Helios should not be cited as a marker of human thymus-derived Tregs. Commentary: helios(+) and helios(-) cells coexist within the natural FOXP3(+) T regulatory cell subset in humans. Front. Immunol. 7, 276 (2016).

  128. 128.

    Scholzen, A., Mittag, D., Rogerson, S. J., Cooke, B. M. & Plebanski, M. Plasmodium falciparum-mediated induction of human CD25Foxp3 CD4 T. cells is independent of direct TCR stimulation and requires IL-2, IL-10 and TGFbeta. PLOS Pathog. 5, e1000543 (2009).

  129. 129.

    Liu, Y. et al. A critical function for TGF-beta signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nat. Immunol. 9, 632–640 (2008).

  130. 130.

    Zheng, Y. et al. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T cell fate. Nature 463, 808–812 (2010).

  131. 131.

    Abel, S. et al. Plasmodium yoelii infection of BALB/c mice results in expansion rather than induction of CD4(+) Foxp3(+) regulatory T cells. Immunology 148, 197–205 (2016).

  132. 132.

    Abel, S. et al. Strong impact of CD4+ Foxp3+ regulatory T cells and limited effect of T cell-derived IL-10 on pathogen clearance during Plasmodium yoelii infection. J. Immunol. 188, 5467–5477 (2012).

  133. 133.

    Sedegah, M. et al. Naturally acquired CD8+ cytotoxic T lymphocytes against the Plasmodium falciparum circumsporozoite protein. J. Immunol. 149, 966–971 (1992).

  134. 134.

    Doolan, D. L. et al. Degenerate cytotoxic T cell epitopes from P. falciparum restricted by multiple HLA-A and HLA-B supertype alleles. Immunity 7, 97–112 (1997).

  135. 135.

    Romero, P. et al. Cloned cytotoxic T cells recognize an epitope in the circumsporozoite protein and protect against malaria. Nature 341, 323–326 (1989).

  136. 136.

    Doolan, D. L. et al. HLA-DR-promiscuous T cell epitopes from Plasmodium falciparum pre-erythrocytic-stage antigens restricted by multiple HLA class II alleles. J. Immunol. 165, 1123–1137 (2000).

  137. 137.

    Doolan, D. L. et al. Identification of Plasmodium falciparum antigens by antigenic analysis of genomic and proteomic data. Proc. Natl Acad. Sci. USA 100, 9952–9957 (2003).

  138. 138.

    Epstein, J. E. et al. Live attenuated malaria vaccine designed to protect through hepatic CD8(+) T cell immunity. Science 334, 475–480 (2011). This study demonstrates the ability of RAS vaccines to stimulate sterilizing immunity to malaria in humans.

  139. 139.

    Hafalla, J. C. et al. Identification of targets of CD8(+) T cell responses to malaria liver stages by genome-wide epitope profiling. PLOS Pathog. 9, e1003303 (2013).

  140. 140.

    Van Braeckel-Budimir, N. & Harty, J. T. CD8 T cell-mediated protection against liver-stage malaria: lessons from a mouse model. Front. Microbiol. 5, 272 (2014).

  141. 141.

    Villarino, N. & Schmidt, N. W. CD8(+) T cell responses to Plasmodium and intracellular parasites. Curr. Immunol. Rev. 9, 169–178 (2013).

  142. 142.

    Medica, D. L. & Sinnis, P. Quantitative dynamics of Plasmodium yoelii sporozoite transmission by infected anopheline mosquitoes. Infect. Immun. 73, 4363–4369 (2005).

  143. 143.

    Churcher, T. S. et al. Probability of transmission of malaria from mosquito to human is regulated by mosquito parasite density in naive and vaccinated hosts. PLOS Pathog. 13, e1006108 (2017).

  144. 144.

    Cowman, A. F., Healer, J., Marapana, D. & Marsh, K. Malaria: biology and disease. Cell 167, 610–624 (2016).

  145. 145.

    Crompton, P. D. et al. Malaria immunity in man and mosquito: insights into unsolved mysteries of a deadly infectious disease. Annu. Rev. Immunol. 32, 157–187 (2014).

  146. 146.

    Miller, J. D. et al. Human effector and memory CD8+ T cell responses to smallpox and yellow fever vaccines. Immunity 28, 710–722 (2008).

  147. 147.

    Sturm, A. et al. Manipulation of host hepatocytes by the malaria parasite for delivery into liver sinusoids. Science 313, 1287–1290 (2006).

  148. 148.

    Tran, T. M. et al. An intensive longitudinal cohort study of Malian children and adults reveals no evidence of acquired immunity to Plasmodium falciparum infection. Clin. Infect. Dis. 57, 40–47 (2013). This study shows that, while repeated exposure to P. falciparum does induce clinical immunity, it does not induce immune responses capable of preventing infection.

  149. 149.

    Offeddu, V., Thathy, V., Marsh, K. & Matuschewski, K. Naturally acquired immune responses against Plasmodium falciparum sporozoites and liver infection. Int. J. Parasitol. 42, 535–548 (2012).

  150. 150.

    Doolan, D. L., Dobano, C. & Baird, J. K. Acquired immunity to malaria. Clin. Microbiol. Rev. 22, 13–36 (2009).

  151. 151.

    Weiss, W. R. & Jiang, C. G. Protective CD8+ T lymphocytes in primates immunized with malaria sporozoites. PLOS ONE 7, e31247 (2012).

  152. 152.

    Weiss, W. R., Sedegah, M., Beaudoin, R. L., Miller, L. H. & Good, M. F. CD8+ T cells (cytotoxic/suppressors) are required for protection in mice immunized with malaria sporozoites. Proc. Natl Acad. Sci. USA 85, 573–576 (1988). This work indicates that CD8 + T cells are critical for mediating immunity to liver-stage malaria.

  153. 153.

    Schmidt, N. W., Butler, N. S., Badovinac, V. P. & Harty, J. T. Extreme CD8 T cell requirements for anti-malarial liver-stage immunity following immunization with radiation attenuated sporozoites. PLOS Pathog. 6, e1000998 (2010).

  154. 154.

    Corradin, G. & Levitskaya, J. Priming of CD8(+) T cell responses to liver stage malaria parasite antigens. Front. Immunol. 5, 527 (2014).

  155. 155.

    Zhang, N. & Bevan, M. J. CD8(+) T cells: foot soldiers of the immune system. Immunity 35, 161–168 (2011).

  156. 156.

    Jung, S. et al. In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens. Immunity 17, 211–220 (2002).

  157. 157.

    Chakravarty, S. et al. CD8+ T lymphocytes protective against malaria liver stages are primed in skin-draining lymph nodes. Nat. Med. 13, 1035–1041 (2007). This study demonstrates the mechanism by which sporozoite-specific CD8 + T cells are primed in the local skin-draining lymph nodes.

  158. 158.

    Radtke, A. J. et al. Lymph-node resident CD8alpha+ dendritic cells capture antigens from migratory malaria sporozoites and induce CD8+ T cell responses. PLOS Pathog. 11, e1004637 (2015).

  159. 159.

    Butler, N. S. et al. Superior antimalarial immunity after vaccination with late liver stage-arresting genetically attenuated parasites. Cell Host Microbe 9, 451–462 (2011). This study shows that live-attenuated Plasmodium parasites that progress further in their liver-stage development and exhibit greater antigenic breadth induce enhanced protection.

  160. 160.

    Kurup, S. P. et al. Monocyte-derived CD11c+ cells acquire Plasmodium from hepatocytes to prime CD8 T cell immunity to liver-stage malaria. Cell Host Microbe (2019). This study demonstrates a fundamental mechanism of priming CD8 + T cell responses against liver-stage malaria.

  161. 161.

    Douradinha, B. et al. Genetically attenuated P36p-deficient Plasmodium berghei sporozoites confer long-lasting and partial cross-species protection. Int. J. Parasitol. 37, 1511–1519 (2007).

  162. 162.

    Kramer, L. D. & Vanderberg, J. P. Intramuscular immunization of mice with irradiated Plasmodium berghei sporozoites. Enhancement of protection with albumin. Am. J. Trop. Med. Hyg. 24, 913–916 (1975).

  163. 163.

    Holz, L. E., Fernandez-Ruiz, D. & Heath, W. R. Protective immunity to liver-stage malaria. Clin. Transl Immunol. 5, e105 (2016).

  164. 164.

    Ryg-Cornejo, V. et al. NK cells and conventional dendritic cells engage in reciprocal activation for the induction of inflammatory responses during Plasmodium berghei ANKA infection. Immunobiology 218, 263–271 (2013).

  165. 165.

    Morrot, A., Hafalla, J. C., Cockburn, I. A., Carvalho, L. H. & Zavala, F. IL-4 receptor expression on CD8+ T cells is required for the development of protective memory responses against liver stages of malaria parasites. J. Exp. Med. 202, 551–560 (2005).

  166. 166.

    da Silva, H. B. et al. Early skin immunological disturbance after Plasmodium-infected mosquito bites. Cell. Immunol. 277, 22–32 (2012).

  167. 167.

    Kimura, K. et al. CD8+ T cells specific for a malaria cytoplasmic antigen form clusters around infected hepatocytes and are protective at the liver stage of infection. Infect. Immun. 81, 3825–3834 (2013).

  168. 168.

    Cockburn, I. A. et al. In vivo imaging of CD8+ T cell-mediated elimination of malaria liver stages. Proc. Natl Acad. Sci. USA 110, 9090–9095 (2013). This work provides insight into the possible mechanisms of CD8 + T cell-mediated elimination of infected hepatocytes in the liver.

  169. 169.

    Harty, J. T., Tvinnereim, A. R. & White, D. W. CD8+ T cell effector mechanisms in resistance to infection. Annu. Rev. Immunol. 18, 275–308 (2000).

  170. 170.

    Halle, S., Halle, O. & Forster, R. Mechanisms and dynamics of T cell-mediated cytotoxicity in vivo. Trends Immunol. 38, 432–443 (2017).

  171. 171.

    Butler, N. S., Schmidt, N. W. & Harty, J. T. Differential effector pathways regulate memory CD8 T cell immunity against Plasmodium berghei versus P. yoelii sporozoites. J. Immunol. 184, 2528–2538 (2010).

  172. 172.

    Morrot, A. & Zavala, F. Regulation of the CD8+ T cell responses against Plasmodium liver stages in mice. Int. J. Parasitol. 34, 1529–1534 (2004).

  173. 173.

    Renggli, J. et al. Elimination of P. berghei liver stages is independent of Fas (CD95/Apo-I) or perforin-mediated cytotoxicity. Parasite Immunol. 19, 145–148 (1997).

  174. 174.

    Nganou-Makamdop, K., van Gemert, G. J., Arens, T., Hermsen, C. C. & Sauerwein, R. W. Long term protection after immunization with P. berghei sporozoites correlates with sustained IFNgamma responses of hepatic CD8+ memory T cells. PLOS ONE 7, e36508 (2012).

  175. 175.

    Clark, I. A., Hunt, N. H., Butcher, G. A. & Cowden, W. B. Inhibition of murine malaria (Plasmodium chabaudi) in vivo by recombinant interferon-gamma or tumor necrosis factor, and its enhancement by butylated hydroxyanisole. J. Immunol. 139, 3493–3496 (1987).

  176. 176.

    Jobe, O. et al. Genetically attenuated Plasmodium berghei liver stages induce sterile protracted protection that is mediated by major histocompatibility complex class I-dependent interferon-gamma-producing CD8+ T cells. J. Infect. Dis. 196, 599–607 (2007).

  177. 177.

    Mellouk, S. et al. Inhibitory activity of interferons and interleukin 1 on the development of Plasmodium falciparum in human hepatocyte cultures. J. Immunol. 139, 4192–4195 (1987).

  178. 178.

    Seguin, M. C. et al. Induction of nitric oxide synthase protects against malaria in mice exposed to irradiated Plasmodium berghei infected mosquitoes: involvement of interferon gamma and CD8+ T cells. J. Exp. Med. 180, 353–358 (1994).

  179. 179.

    Chakravarty, S., Baldeviano, G. C., Overstreet, M. G. & Zavala, F. Effector CD8+ T lymphocytes against liver stages of Plasmodium yoelii do not require gamma interferon for antiparasite activity. Infect. Immun. 76, 3628–3631 (2008).

  180. 180.

    Doolan, D. L. & Hoffman, S. L. The complexity of protective immunity against liver-stage malaria. J. Immunol. 165, 1453–1462 (2000).

  181. 181.

    Schmidt, N. W., Butler, N. S. & Harty, J. T. Plasmodium-host interactions directly influence the threshold of memory CD8 T cells required for protective immunity. J. Immunol. 186, 5873–5884 (2011).

  182. 182.

    Schmidt, N. W. et al. Memory CD8 T cell responses exceeding a large but definable threshold provide long-term immunity to malaria. Proc. Natl Acad. Sci. USA 105, 14017–14022 (2008).

  183. 183.

    Fernandez-Ruiz, D. et al. Liver-resident memory CD8(+) T cells form a front-line defense against malaria liver-stage infection. Immunity 45, 889–902 (2016). This seminal study demonstrates the role of Plasmodium antigen-specific, non-recirculating (resident) CD8 + T cells in the liver in protection from liver-stage malaria.

  184. 184.

    Gola, A. et al. Prime and target immunization protects against liver-stage malaria in mice. Sci. Transl Med. 10, eaap9128 (2018).

  185. 185.

    Olsen, T. M., Stone, B. C., Chuenchob, V. & Murphy, S. C. Prime-and-trap malaria vaccination to generate protective CD8(+) liver-resident memory T cells. J. Immunol. 201, 1984–1993 (2018).

  186. 186.

    Holz, L. E. et al. CD8(+) T cell activation leads to constitutive formation of liver tissue-resident memory T cells that seed a large and flexible niche in the liver. Cell Rep. 25, 68–79 (2018).

  187. 187.

    McNamara, H. A. et al. Up-regulation of LFA-1 allows liver-resident memory T cells to patrol and remain in the hepatic sinusoids. Sci. Immunol. 2, eaaj1996 (2017).

  188. 188.

    Schenkel, J. M., Fraser, K. A., Vezys, V. & Masopust, D. Sensing and alarm function of resident memory CD8(+) T cells. Nat. Immunol. 14, 509–513 (2013).

  189. 189.

    Kumar, S. & Miller, L. H. Cellular mechanisms in immunity to blood stage infection. Immunol. Lett. 25, 109–114 (1990).

  190. 190.

    Vinetz, J. M. et al. Adoptive transfer of CD8+ T cells from immune animals does not transfer immunity to blood stage Plasmodium yoelii malaria. J. Immunol. 144, 1069–1074 (1990).

  191. 191.

    Miyakoda, M. et al. Development of memory CD8+ T cells and their recall responses during blood-stage infection with Plasmodium berghei ANKA. J. Immunol. 189, 4396–4404 (2012).

  192. 192.

    Chandele, A., Mukerjee, P., Das, G., Ahmed, R. & Chauhan, V. S. Phenotypic and functional profiling of malaria-induced CD8 and CD4 T cells during blood-stage infection with Plasmodium yoelii. Immunology 132, 273–286 (2011).

  193. 193.

    Lundie, R. J. et al. Blood-stage Plasmodium infection induces CD8+ T lymphocytes to parasite-expressed antigens, largely regulated by CD8alpha+ dendritic cells. Proc. Natl Acad. Sci. USA 105, 14509–14514 (2008).

  194. 194.

    Junqueira, C. et al. Cytotoxic CD8(+) T cells recognize and kill Plasmodium vivax-infected reticulocytes. Nat. Med. 24, 1330–1336 (2018). This study investigates the mechanism by which CD8 + T cells contribute to the control of blood-stage malaria.

  195. 195.

    Swanson, P. A. 2nd et al. CD8+ T cells induce fatal brainstem pathology during cerebral malaria via luminal antigen-specific engagement of brain vasculature. PLOS Pathog. 12, e1006022 (2016).

  196. 196.

    Belnoue, E. et al. On the pathogenic role of brain-sequestered alphabeta CD8+ T cells in experimental cerebral malaria. J. Immunol. 169, 6369–6375 (2002).

  197. 197.

    Nitcheu, J. et al. Perforin-dependent brain-infiltrating cytotoxic CD8+ T lymphocytes mediate experimental cerebral malaria pathogenesis. J. Immunol. 170, 2221–2228 (2003).

  198. 198.

    Randall, L. M. et al. Common strategies to prevent and modulate experimental cerebral malaria in mouse strains with different susceptibilities. Infect. Immun. 76, 3312–3320 (2008).

  199. 199.

    Claser, C. et al. CD8+ T cells and IFN-gamma mediate the time-dependent accumulation of infected red blood cells in deep organs during experimental cerebral malaria. PLOS ONE 6, e18720 (2011).

  200. 200.

    Haque, A. et al. Granzyme B expression by CD8+ T cells is required for the development of experimental cerebral malaria. J. Immunol. 186, 6148–6156 (2011).

  201. 201.

    Farooq, U., Dubey, M. L., Shrivastava, S. K. & Mahajan, R. C. Genetic polymorphism in Plasmodium falciparum: differentiation of parasite isolates of high & low virulence by RAPD. Indian J. Med. Res. 136, 292–295 (2012).

  202. 202.

    Kyriacou, H. M. et al. Differential var gene transcription in Plasmodium falciparum isolates from patients with cerebral malaria compared to hyperparasitaemia. Mol. Biochem. Parasitol. 150, 211–218 (2006).

  203. 203.

    Bertin, G. I. et al. Proteomic analysis of Plasmodium falciparum parasites from patients with cerebral and uncomplicated malaria. Sci. Rep. 6, 26773 (2016).

  204. 204.

    Mazier, D., Nitcheu, J. & Idrissa-Boubou, M. Cerebral malaria and immunogenetics. Parasite Immunol. 22, 613–623 (2000).

  205. 205.

    Mackey, L. J., Hochmann, A., June, C. H., Contreras, C. E. & Lambert, P. H. Immunopathological aspects of Plasmodium berghei infection in five strains of mice. II. Immunopathology of cerebral and other tissue lesions during the infection. Clin. Exp. Immunol. 42, 412–420 (1980).

  206. 206.

    Van Braeckel-Budimir, N. et al. A T cell receptor locus harbors a malaria-specific immune response gene. Immunity 47, 835–847 (2017).

  207. 207.

    White, N. J., Turner, G. D., Medana, I. M., Dondorp, A. M. & Day, N. P. The murine cerebral malaria phenomenon. Trends Parasitol. 26, 11–15 (2010).

  208. 208.

    Hunt, N. H. et al. Murine cerebral malaria: the whole story. Trends Parasitol. 26, 272–274 (2010).

  209. 209.

    Chien, Y. H., Meyer, C. & Bonneville, M. γδ T cells: first line of defense and beyond. Annu. Rev. Immunol. 32, 121–155 (2014).

  210. 210.

    Holtmeier, W. & Kabelitz, D. γδ T cells link innate and adaptive immune responses. Chem. Immunol. Allergy 86, 151–183 (2005).

  211. 211.

    Hayday, A. C. γδ cells: a right time and a right place for a conserved third way of protection. Annu. Rev. Immunol. 18, 975–1026 (2000).

  212. 212.

    Carding, S. R. & Egan, P. J. Gammadelta T cells: functional plasticity and heterogeneity. Nat. Rev. Immunol. 2, 336–345 (2002).

  213. 213.

    Zhao, Y., Niu, C. & Cui, J. Gamma-delta (γδ) T cells: friend or foe in cancer development? J. Transl Med. 16, 3 (2018).

  214. 214.

    Kurup, S. P. & Harty, J. T. γδ T cells and immunity to human malaria in endemic regions. Ann. Transl Med. 3, S22 (2015).

  215. 215.

    Hviid, L. et al. Perturbation and proinflammatory type activation of V delta 1(+) gamma delta T cells in African children with Plasmodium falciparum malaria. Infect. Immun. 69, 3190–3196 (2001).

  216. 216.

    Langhorne, J., Morris-Jones, S., Casabo, L. G. & Goodier, M. The response of gamma delta T cells in malaria infections: a hypothesis. Res. Immunol. 145, 429–436 (1994).

  217. 217.

    Roussilhon, C., Agrapart, M., Ballet, J. J. & Bensussan, A. T lymphocytes bearing the gamma delta T cell receptor in patients with acute Plasmodium falciparum malaria. J. Infect. Dis. 162, 283–285 (1990).

  218. 218.

    Teirlinck, A. C. et al. Longevity and composition of cellular immune responses following experimental Plasmodium falciparum malaria infection in humans. PLOS Pathog. 7, e1002389 (2011).

  219. 219.

    D’Ombrain, M. C. et al. Association of early interferon-gamma production with immunity to clinical malaria: a longitudinal study among Papua New Guinean children. Clin. Infect. Dis. 47, 1380–1387 (2008).

  220. 220.

    Goodier, M. et al. Gamma delta T cells in the peripheral blood of individuals from an area of holoendemic Plasmodium falciparum transmission. Trans. R. Soc. Trop. Med. Hyg. 87, 692–696 (1993).

  221. 221.

    Jagannathan, P. et al. Loss and dysfunction of Vdelta2(+) γδ T cells are associated with clinical tolerance to malaria. Sci. Transl Med. 6, 251ra117 (2014). This work investigates the role of γδ T cells in blood-stage malaria in humans in a malaria-endemic region and possible disease outcomes.

  222. 222.

    De Rosa, S. C. et al. Ontogeny of gamma delta T cells in humans. J. Immunol. 172, 1637–1645 (2004).

  223. 223.

    Dondorp, A. M. et al. The relationship between age and the manifestations of and mortality associated with severe malaria. Clin. Infect. Dis. 47, 151–157 (2008).

  224. 224.

    Schwartz, E., Sadetzki, S., Murad, H. & Raveh, D. Age as a risk factor for severe Plasmodium falciparum malaria in nonimmune patients. Clin. Infect. Dis. 33, 1774–1777 (2001).

  225. 225.

    Inoue, S. I., Niikura, M., Asahi, H., Kawakami, Y. & Kobayashi, F. γδ T cells modulate humoral immunity against Plasmodium berghei infection. Immunology 155, 519–532 (2018).

  226. 226.

    Mamedov, M. R. et al. A macrophage colony-stimulating-factor-producing γδ T cell subset prevents malarial parasitemic recurrence. Immunity 48, 350–363 (2018). This study identifies a protective, M-CSF-producing γδ T cell subset in the later stage of malaria infection.

  227. 227.

    Zaidi, I. et al. γδ T cells are required for the induction of sterile immunity during irradiated sporozoite vaccinations. J. Immunol. 199, 3781–3788 (2017).

  228. 228.

    Zeng, X. et al. γδ T cells recognize a microbial encoded B cell antigen to initiate a rapid antigen-specific interleukin-17 response. Immunity 37, 524–534 (2012).

  229. 229.

    Cai, Y. et al. Differential developmental requirement and peripheral regulation for dermal Vgamma4 and Vgamma6T17 cells in health and inflammation. Nat. Commun. 5, 3986 (2014).

  230. 230.

    Paul, S. & Lal, G. Regulatory and effector functions of gamma-delta (γδ) T cells and their therapeutic potential in adoptive cellular therapy for cancer. Int. J. Cancer 139, 976–985 (2016).

  231. 231.

    Constant, P. et al. Stimulation of human gamma delta T cells by nonpeptidic mycobacterial ligands. Science 264, 267–270 (1994).

  232. 232.

    Sheridan, B. S. et al. γδ T cells exhibit multifunctional and protective memory in intestinal tissues. Immunity 39, 184–195 (2013).

  233. 233.

    Elloso, M. M., van der Heyde, H. C., vande Waa, J. A., Manning, D. D. & Weidanz, W. P. Inhibition of Plasmodium falciparum in vitro by human gamma delta T cells. J. Immunol. 153, 1187–1194 (1994).

  234. 234.

    Hensmann, M. & Kwiatkowski, D. Cellular basis of early cytokine response to Plasmodium falciparum. Infect. Immun. 69, 2364–2371 (2001).

  235. 235.

    Behr, C. et al. Plasmodium falciparum stimuli for human γδ T cells are related to phosphorylated antigens of mycobacteria. Infect. Immun. 64, 2892–2896 (1996).

  236. 236.

    Elloso, M. M., van der Heyde, H. C., Troutt, A., Manning, D. D. & Weidanz, W. P. Human gamma delta T cell subset-proliferative response to malarial antigen in vitro depends on CD4+ T cells or cytokines that signal through components of the IL-2R. J. Immunol. 157, 2096–2102 (1996).

  237. 237.

    Jones, S. M., Goodier, M. R. & Langhorne, J. The response of gamma delta T cells to Plasmodium falciparum is dependent on activated CD4+ T cells and the recognition of MHC class I molecules. Immunology 89, 405–412 (1996).

  238. 238.

    Pichyangkul, S., Saengkrai, P., Yongvanitchit, K., Stewart, A. & Heppner, D. G. Activation of γδ T cells in malaria: interaction of cytokines and a schizont-associated Plasmodium falciparum antigen. J. Infect. Dis. 176, 233–241 (1997).

  239. 239.

    Cockburn, I. A. & Seder, R. A. Malaria prevention: from immunological concepts to effective vaccines and protective antibodies. Nat. Immunol. 19, 1199–1211 (2018).

  240. 240.

    Draper, S. J. et al. Malaria vaccines: recent advances and new horizons. Cell Host Microbe 24, 43–56 (2018).

  241. 241.

    Butler, N. S., Vaughan, A. M., Harty, J. T. & Kappe, S. H. Whole parasite vaccination approaches for prevention of malaria infection. Trends Immunol. 33, 247–254 (2012).

  242. 242.

    Hoffman, S. L., Vekemans, J., Richie, T. L. & Duffy, P. E. The march toward malaria vaccines. Am. J. Prev. Med. 49, S319–S333 (2015).

  243. 243.

    Hill, A. V. Vaccines against malaria. Phil. Trans. R. Soc. B 366, 2806–2814 (2011).

  244. 244.

    Ewer, K. J. et al. Progress with viral vectored malaria vaccines: A multi-stage approach involving “unnatural immunity”. Vaccine 33, 7444–7451 (2015).

  245. 245.

    Li, Y. et al. Enhancing immunogenicity and transmission-blocking activity of malaria vaccines by fusing Pfs25 to IMX313 multimerization technology. Sci. Rep. 6, 18848 (2016).

  246. 246.

    Doll, K. L., Pewe, L. L., Kurup, S. P. & Harty, J. T. Discriminating protective from nonprotective Plasmodium-specific CD8+ T cell responses. J. Immunol. 196, 4253–4262 (2016).

  247. 247.

    Lau, L. S. et al. CD8+ T cells from a novel T cell receptor transgenic mouse induce liver-stage immunity that can be boosted by blood-stage infection in rodent malaria. PLOS Pathog. 10, e1004135 (2014).

  248. 248.

    Fernandez-Ruiz, D. et al. Development of a novel CD4(+) TCR transgenic line that reveals a dominant role for CD8(+) dendritic cells and CD40 signaling in the generation of helper and CTL responses to blood-stage malaria. J. Immunol. 199, 4165–4179 (2017).

  249. 249.

    Shekalaghe, S. et al. Controlled human malaria infection of Tanzanians by intradermal injection of aseptic, purified, cryopreserved Plasmodium falciparum sporozoites. Am. J. Trop. Med. Hyg. 91, 471–480 (2014).

  250. 250.

    Hodgson, S. H. et al. Evaluating controlled human malaria infection in Kenyan adults with varying degrees of prior exposure to Plasmodium falciparum using sporozoites administered by intramuscular injection. Front. Microbiol. 5, 686 (2014).

  251. 251.

    Obiero, J. M. et al. Impact of malaria preexposure on antiparasite cellular and humoral immune responses after controlled human malaria infection. Infect. Immun. 83, 2185–2196 (2015).

Download references


The authors apologize to the countless researchers whose contributions are not discussed in this manuscript owing to space limitations. They also thank the Butler and Harty laboratory members for helpful discussions. Work in the laboratory of N.S.B. is supported by grants from the US National Institutes of Health (NIH) (AI125446 and AI127481). Work in the laboratory of J.T.H. is supported by grants from the NIH (AI42767, AI95178, AI100527 and AI114543).

Reviewer information

Nature Reviews Immunology thanks A. Haque, M. Good and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

All authors contributed to the discussion of content and to the writing and the editing of the manuscript.

Competing interests

The authors declare no competing interests.

Correspondence to John T. Harty.



A Plasmodium parasite life form transmitted by mosquito bite and capable of initiating the asexual cycle of growth and differentiation in the vertebrate host.


Plasmodium parasite life forms that first develop in infected hepatocytes and are capable of initiating either sexual or asexual cycles of development in host red blood cells.


Host cell-derived, membrane-bound structure containing multiple merozoites that buds from infected hepatocytes during Plasmodium egress from the liver. Merosomes release merozoites into circulation after rupture.


The candidate anti-malarial vaccine furthest along in global development. RTS,S comprises two subdomains of the Plasmodium falciparum circumsporozoite protein (CSP) that are associated with units of the hepatitis B surface antigen and formulated with the adjuvant AS01 (3-O-desacyl-4′-monophosphoryl lipid A and the saponin QS-21). Infection is prevented by inducing antibodies that either immobilize sporozoites in the skin or prevent sporozoites from infecting the liver.

Circumsporozoite protein

(CSP). Immunodominant, high-density surface antigen expressed by Plasmodium sporozoites that is the target of humoral and cellular immune responses that either block sporozoite infection of the liver or eliminate infected hepatocytes, respectively.

Chemoprophylaxis and sporozoite (CPS) immunization

A vaccination strategy whereby virulent sporozoites are delivered by either mosquito bites or needle injection with prophylactic delivery of a drug targeting Plasmodium blood stages. Parasites initiate and complete liver-stage development, release merozoites and initiate the first wave of blood-stage infection before being eliminated by the drug. Vaccinated individuals are thereby exposed to antigens that derive from multiple parasite life cycle stages while remaining protected against clinical disease by the anti-blood-stage drug.


Non-photosynthetic organelles that characterize protists within the phylum Apicomplexa and are likely derived from an algal endosymbiont. All apicoplast functions are not fully known, but defined activities primarily relate to essential metabolic pathways necessary for the viability of Plasmodium and other apicomplexans.

Rights and permissions

To obtain permission to re-use content from this article visit RightsLink.

About this article

Fig. 1: Plasmodium life cycle.
Fig. 2: Overview of tissue-specific, T cell-mediated immune resistance networks during Plasmodium infection.