Much effort has been devoted to the design of vaccines that induce adaptive cellular immunity, in particular CD8+ T cells, which have a central role in the host response to viral infections and cancers. To date, however, the development of effective T cell vaccines remains elusive. This is due, in part, to the lack of clearly defined correlates of protection and the inherent difficulties that hinder full characterization of the determinants of successful T cell immunity in humans. Recent data from the disparate fields of infectious disease and tumor immunology have converged, with an emphasis on the functional attributes of individual antigen-specific T cell clonotypes, to provide a better understanding of CD8+ T cell efficacy. This new knowledge paves the way to the design of more effective T cell vaccines and highlights the importance of comprehensive immunomonitoring.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Nature Communications Open Access 24 November 2021
Communications Biology Open Access 10 June 2021
The armed oncolytic adenovirus ZD55-IL-24 eradicates melanoma by turning the tumor cells from the self-state into the nonself-state besides direct killing
Cell Death & Disease Open Access 30 November 2020
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Mattapallil, J.J. et al. Vaccination preserves CD4 memory T cells during acute simian immunodeficiency virus challenge. J. Exp. Med. 203, 1533–1541 (2006).
Migueles, S.A. et al. HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long-term nonprogressors. Proc. Natl. Acad. Sci. USA 97, 2709–2714 (2000).
Betts, M.R. et al. Analysis of total human immunodeficiency virus (HIV)-specific CD4+ and CD8+ T cell responses: relationship to viral load in untreated HIV infection. J. Virol. 75, 11983–11991 (2001).
Lee, P.P. et al. Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients. Nat. Med. 5, 677–685 (1999).
Dunbar, P.R. et al. A shift in the phenotype of melan-A–specific CTL identifies melanoma patients with an active tumor-specific immune response. J. Immunol. 165, 6644–6652 (2000).
Appay, V. et al. HIV-specific CD8+ T cells produce antiviral cytokines but are impaired in cytolytic function. J. Exp. Med. 192, 63–75 (2000).
Champagne, P. et al. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 410, 106–111 (2001).
Speiser, D.E. et al. In vivo activation of melanoma-specific CD8+ T cells by endogenous tumor antigen and peptide vaccines. A comparison to virus-specific T cells. Eur. J. Immunol. 32, 731–741 (2002).
Mortarini, R. et al. Lack of terminally differentiated tumor-specific CD8+ T cells at tumor site in spite of antitumor immunity to self antigens in human metastatic melanoma. Cancer Res. 63, 2535–2545 (2003).
Appay, V. et al. Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat. Med. 8, 379–385 (2002).
Betts, M.R. et al. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 107, 4781–4789 (2006).
Wherry, E.J. et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat. Immunol. 4, 225–234 (2003).
Gattinoni, L. et al. Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. J. Clin. Invest. 115, 1616–1626 (2005).
Sacre, K. et al. Repertoire, diversity, and differentiation of specific CD8 T cells are associated with immune protection against human cytomegalovirus disease. J. Exp. Med. 201, 1999–2010 (2005).
Berger, C. et al. Adoptive transfer of effector CD8 T cells derived from central memory cells establishes persistent T cell memory in primates. J. Clin. Invest. 118, 294–305 (2008).
Day, C.L. et al. PD-1 expression on HIV-specific T cells is associated with T cell exhaustion and disease progression. Nature 443, 350–354 (2006).
Trautmann, L. et al. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat. Med. 12, 1198–1202 (2006).
Petrovas, C. et al. PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J. Exp. Med. 203, 2281–2292 (2006).
Sauce, D. et al. PD-1 expression on human CD8 T cells depends on both state of differentiation and activation status. AIDS 21, 2005–2013 (2007).
Migueles, S.A. et al. HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat. Immunol. 3, 1061–1068 (2002).
Zhou, J. et al. Telomere length of transferred lymphocytes correlates with in vivo persistence and tumor regression in melanoma patients receiving cell transfer therapy. J. Immunol. 175, 7046–7052 (2005).
Harari, A., Petitpierre, S., Vallelian, F. & Pantaleo, G. Skewed representation of functionally distinct populations of virus-specific CD4 T cells in HIV-1–infected subjects with progressive disease: changes after antiretroviral therapy. Blood 103, 966–972 (2004).
Almeida, J.R. et al. Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnover. J. Exp. Med. 204, 2473–2485 (2007).
Beveridge, N.E. et al. Immunisation with BCG and recombinant MVA85A induces long-lasting, polyfunctional Mycobacterium tuberculosis–specific CD4+ memory T lymphocyte populations. Eur. J. Immunol. 37, 3089–3100 (2007).
Darrah, P.A. et al. Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major. Nat. Med. 13, 843–850 (2007).
Precopio, M.L. et al. Immunization with vaccinia virus induces polyfunctional and phenotypically distinctive CD8+ T cell responses. J. Exp. Med. 204, 1405–1416 (2007).
Derby, M., Alexander-Miller, M., Tse, R. & Berzofsky, J. High-avidity CTL exploit two complementary mechanisms to provide better protection against viral infection than low-avidity CTL. J. Immunol. 166, 1690–1697 (2001).
Bennett, M.S., Ng, H.L., Dagarag, M., Ali, A. & Yang, O.O. Epitope-dependent avidity thresholds for cytotoxic T-lymphocyte clearance of virus-infected cells. J. Virol. 81, 4973–4980 (2007).
Speiser, D.E., Kyburz, D., Stubi, U., Hengartner, H. & Zinkernagel, R.M. Discrepancy between in vitro measurable and in vivo virus-neutralizing cytotoxic T cell reactivities. Low T cell receptor specificity and avidity sufficient for in vitro proliferation or cytotoxicity to peptide-coated target cells but not for in vivo protection. J. Immunol. 149, 972–980 (1992).
Alexander-Miller, M.A., Leggatt, G.R. & Berzofsky, J.A. Selective expansion of high- or low-avidity cytotoxic T lymphocytes and efficacy for adoptive immunotherapy. Proc. Natl. Acad. Sci. USA 93, 4102–4107 (1996).
Messaoudi, I., Guevara Patino, J.A., Dyall, R., LeMaoult, J. & Nikolich-Zugich, J. Direct link between MHC polymorphism, T cell avidity and diversity in immune defense. Science 298, 1797–1800 (2002).
Yee, C., Savage, P.A., Lee, P.P., Davis, M.M. & Greenberg, P.D. Isolation of high avidity melanoma-reactive CTL from heterogeneous populations using peptide-MHC tetramers. J. Immunol. 162, 2227–2234 (1999).
Zeh, H.J. III, Perry-Lalley, D., Dudley, M.E., Rosenberg, S.A. & Yang, J.C. High avidity CTLs for two self-antigens demonstrate superior in vitro and in vivo antitumor efficacy. J. Immunol. 162, 989–994 (1999).
Dutoit, V. et al. Heterogeneous T cell response to MAGE-A10254–262: high avidity–specific cytolytic T lymphocytes show superior antitumor activity. Cancer Res. 61, 5850–5856 (2001).
Belyakov, I.M. et al. Impact of vaccine-induced mucosal high-avidity CD8+ CTLs in delay of AIDS viral dissemination from mucosa. Blood 107, 3258–3264 (2006).
O'Connor, D.H. et al. Acute phase cytotoxic T lymphocyte escape is a hallmark of simian immunodeficiency virus infection. Nat. Med. 8, 493–499 (2002).
Saez-Cirion, A. et al. HIV controllers exhibit potent CD8 T cell capacity to suppress HIV infection ex vivo and peculiar cytotoxic T lymphocyte activation phenotype. Proc. Natl. Acad. Sci. USA 104, 6776–6781 (2007).
Cawthon, A.G., Lu, H. & Alexander-Miller, M.A. Peptide requirement for CTL activation reflects the sensitivity to CD3 engagement: correlation with CD8αβ versus CD8αα expression. J. Immunol. 167, 2577–2584 (2001).
Schamel, W.W. et al. Coexistence of multivalent and monovalent TCRs explains high sensitivity and wide range of response. J. Exp. Med. 202, 493–503 (2005).
Park, J.H. et al. 'Coreceptor tuning': cytokine signals transcriptionally tailor CD8 coreceptor expression to the self-specificity of the TCR. Nat. Immunol. 8, 1049–1059 (2007).
Viola, A. & Lanzavecchia, A. T cell activation determined by T cell receptor number and tunable thresholds. Science 273, 104–106 (1996).
Valitutti, S., Muller, S., Dessing, M. & Lanzavecchia, A. Different responses are elicited in cytotoxic T lymphocytes by different levels of T cell receptor occupancy. J. Exp. Med. 183, 1917–1921 (1996).
Price, D.A. et al. Antigen-specific release of β-chemokines by anti–HIV-1 cytotoxic T lymphocytes. Curr. Biol. 8, 355–358 (1998).
Betts, M.R. et al. The functional profile of primary human antiviral CD8+ T cell effector activity is dictated by cognate peptide concentration. J. Immunol. 172, 6407–6417 (2004).
La Gruta, N.L., Turner, S.J. & Doherty, P.C. Hierarchies in cytokine expression profiles for acute and resolving influenza virus–specific CD8+ T cell responses: correlation of cytokine profile and TCR avidity. J. Immunol. 172, 5553–5560 (2004).
Seder, R.A., Darrah, P.A. & Roederer, M. T cell quality in memory and protection: implications for vaccine design. Nat. Rev. Immunol. 8, 247–258 (2008).
Huse, M. et al. Spatial and temporal dynamics of T cell receptor signaling with a photoactivatable agonist. Immunity 27, 76–88 (2007).
Dzutsev, A.H., Belyakov, I.M., Isakov, D.V., Margulies, D.H. & Berzofsky, J.A. Avidity of CD8 T cells sharpens immunodominance. Int. Immunol. 19, 497–507 (2007).
Price, D.A. et al. Avidity for antigen shapes clonal dominance in CD8+ T cell populations specific for persistent DNA viruses. J. Exp. Med. 202, 1349–1361 (2005).
Trautmann, L. et al. Selection of T cell clones expressing high-affinity public TCRs within human cytomegalovirus–specific CD8 T cell responses. J. Immunol. 175, 6123–6132 (2005).
Bihl, F. et al. Impact of HLA-B alleles, epitope binding affinity, functional avidity, and viral coinfection on the immunodominance of virus-specific CTL responses. J. Immunol. 176, 4094–4101 (2006).
Speiser, D.E. et al. A novel approach to characterize clonality and differentiation of human melanoma-specific T cell responses: spontaneous priming and efficient boosting by vaccination. J. Immunol. 177, 1338–1348 (2006).
Effros, R.B. & Pawelec, G. Replicative senescence of T cells: does the Hayflick Limit lead to immune exhaustion? Immunol. Today 18, 450–454 (1997).
Lichterfeld, M. et al. Selective depletion of high-avidity human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T cells after early HIV-1 infection. J. Virol. 81, 4199–4214 (2007).
Vezys, V. et al. Continuous recruitment of naive T cells contributes to heterogeneity of antiviral CD8 T cells during persistent infection. J. Exp. Med. 203, 2263–2269 (2006).
Davenport, M.P., Fazou, C., McMichael, A.J. & Callan, M.F. Clonal selection, clonal senescence, and clonal succession: the evolution of the T cell response to infection with a persistent virus. J. Immunol. 168, 3309–3317 (2002).
Douek, D.C. et al. A novel approach to the analysis of specificity, clonality, and frequency of HIV-specific T cell responses reveals a potential mechanism for control of viral escape. J. Immunol. 168, 3099–3104 (2002).
Price, D.A. et al. T cell receptor recognition motifs govern immune escape patterns in acute SIV infection. Immunity 21, 793–803 (2004).
Lichterfeld, M. et al. A viral CTL escape mutation leading to immunoglobulin-like transcript 4–mediated functional inhibition of myelomonocytic cells. J. Exp. Med. 204, 2813–2824 (2007).
Davenport, M.P., Price, D.A. & McMichael, A.J. The T cell repertoire in infection and vaccination: implications for control of persistent viruses. Curr. Opin. Immunol. 19, 294–300 (2007).
Douek, D.C., Picker, L.J. & Koup, R.A. T cell dynamics in HIV-1 infection. Annu. Rev. Immunol. 21, 265–304 (2003).
Douek, D.C. et al. Changes in thymic function with age and during the treatment of HIV infection. Nature 396, 690–695 (1998).
Dion, M.L. et al. HIV infection rapidly induces and maintains a substantial suppression of thymocyte proliferation. Immunity 21, 757–768 (2004).
Jenkins, M., Hanley, M.B., Moreno, M.B., Wieder, E. & McCune, J.M. Human immunodeficiency virus-1 infection interrupts thymopoiesis and multilineage hematopoiesis in vivo. Blood 91, 2672–2678 (1998).
Picker, L.J. et al. Insufficient production and tissue delivery of CD4+ memory T cells in rapidly progressive simian immunodeficiency virus infection. J. Exp. Med. 200, 1299–1314 (2004).
Letvin, N.L. et al. Preserved CD4+ central memory T cells and survival in vaccinated SIV-challenged monkeys. Science 312, 1530–1533 (2006).
Dudley, M.E. et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298, 850–854 (2002).
Johnson, L.A. et al. Gene transfer of tumor-reactive TCR confers both high avidity and tumor reactivity to nonreactive peripheral blood mononuclear cells and tumor-infiltrating lymphocytes. J. Immunol. 177, 6548–6559 (2006).
Morgan, R.A. et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314, 126–129 (2006).
Walter, S. et al. Cutting edge: predetermined avidity of human CD8 T cells expanded on calibrated MHC–anti-CD28–coated microspheres. J. Immunol. 171, 4974–4978 (2003).
Bullock, T.N., Mullins, D.W. & Engelhard, V.H. Antigen density presented by dendritic cells in vivo differentially affects the number and avidity of primary, memory, and recall CD8+ T cells. J. Immunol. 170, 1822–1829 (2003).
Kroger, C.J. & Alexander-Miller, M.A. Cutting edge: CD8+ T cell clones possess the potential to differentiate into both high- and low-avidity effector cells. J. Immunol. 179, 748–751 (2007).
Monsurro, V. et al. Quiescent phenotype of tumor-specific CD8+ T cells following immunization. Blood 104, 1970–1978 (2004).
Narayan, S., Choyce, A., Fernando, G.J. & Leggatt, G.R. Secondary immunisation with high-dose heterologous peptide leads to CD8 T cell populations with reduced functional avidity. Eur. J. Immunol. 37, 406–415 (2007).
Estcourt, M.J. et al. Prime-boost immunization generates a high frequency, high-avidity CD8+ cytotoxic T lymphocyte population. Int. Immunol. 14, 31–37 (2002).
Oh, S. et al. Selective induction of high avidity CTL by altering the balance of signals from APC. J. Immunol. 170, 2523–2530 (2003).
Hodge, J.W., Chakraborty, M., Kudo-Saito, C., Garnett, C.T. & Schlom, J. Multiple costimulatory modalities enhance CTL avidity. J. Immunol. 174, 5994–6004 (2005).
Maher, J., Brentjens, R.J., Gunset, G., Riviere, I. & Sadelain, M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRζ /CD28 receptor. Nat. Biotechnol. 20, 70–75 (2002).
Finney, H.M., Akbar, A.N. & Lawson, A.D. Activation of resting human primary T cells with chimeric receptors: costimulation from CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCR ζ chain. J. Immunol. 172, 104–113 (2004).
Sedlik, C. et al. In vivo induction of a high-avidity, high-frequency cytotoxic T-lymphocyte response is associated with antiviral protective immunity. J. Virol. 74, 5769–5775 (2000).
Castellino, F. & Germain, R.N. Cooperation between CD4+ and CD8+ T cells: when, where, and how. Annu. Rev. Immunol. 24, 519–540 (2006).
Douek, D.C. et al. HIV preferentially infects HIV-specific CD4+ T cells. Nature 417, 95–98 (2002).
Zhou, G., Drake, C.G. & Levitsky, H.I. Amplification of tumor-specific regulatory T cells following therapeutic cancer vaccines. Blood 107, 628–636 (2006).
Williams, M.A. & Bevan, M.J. Effector and memory CTL differentiation. Annu. Rev. Immunol. 25, 171–192 (2007).
Speiser, D.E. et al. Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA and CpG oligodeoxynucleotide 7909. J. Clin. Invest. 115, 739–746 (2005).
Wille-Reece, U. et al. Toll-like receptor agonists influence the magnitude and quality of memory T cell responses after prime-boost immunization in nonhuman primates. J. Exp. Med. 203, 1249–1258 (2006).
Trumpfheller, C. et al. The microbial mimic poly IC induces durable and protective CD4+ T cell immunity together with a dendritic cell targeted vaccine. Proc. Natl. Acad. Sci. USA 105, 2574–2579 (2008).
Belyakov, I.M., Isakov, D., Zhu, Q., Dzutsev, A. & Berzofsky, J.A. A novel functional CTL avidity/activity compartmentalization to the site of mucosal immunization contributes to protection of macaques against simian/human immunodeficiency viral depletion of mucosal CD4+ T cells. J. Immunol. 178, 7211–7221 (2007).
Ranasinghe, C. et al. Mucosal HIV-1 pox virus prime-boost immunization induces high-avidity CD8+ T cells with regime-dependent cytokine/granzyme B profiles. J. Immunol. 178, 2370–2379 (2007).
Critchfield, J.W. et al. Multifunctional human immunodeficiency virus (HIV) Gag-specific CD8+ T cell responses in rectal mucosa and peripheral blood mononuclear cells during chronic HIV type 1 infection. J. Virol. 81, 5460–5471 (2007).
Zhou, J., Dudley, M.E., Rosenberg, S.A. & Robbins, P.F. Selective growth, in vitro and in vivo, of individual T cell clones from tumor-infiltrating lymphocytes obtained from patients with melanoma. J. Immunol. 173, 7622–7629 (2004).
Appay, V. et al. New generation vaccine induces effective melanoma-specific CD8+ T cells in the circulation but not in the tumor site. J. Immunol. 177, 1670–1678 (2006).
Kiepiela, P. et al. CD8+ T cell responses to different HIV proteins have discordant associations with viral load. Nat. Med. 13, 46–53 (2007).
Sacha, J.B. et al. Gag-specific CD8+ T lymphocytes recognize infected cells before AIDS-virus integration and viral protein expression. J. Immunol. 178, 2746–2754 (2007).
Friedrich, T.C. et al. Subdominant CD8+ T cell responses are involved in durable control of AIDS virus replication. J. Virol. 81, 3465–3476 (2007).
Appay, V. et al. Decreased specific CD8+ T cell cross-reactivity of antigen recognition following vaccination with Melan-A peptide. Eur. J. Immunol. 36, 1805–1814 (2006).
Stuge, T.B. et al. Diversity and recognition efficiency of T cell responses to cancer. PLoS Med. 1, e28 (2004).
Speiser, D.E. et al. Unmodified self antigen triggers human CD8 T cells with stronger tumor reactivity than altered antigen. Proc. Natl. Acad. Sci. USA 105, 3849–3854 (2008).
Betts, M.R. et al. Characterization of functional and phenotypic changes in anti-Gag vaccine-induced T cell responses and their role in protection after HIV-1 infection. Proc. Natl. Acad. Sci. USA 102, 4512–4517 (2005).
Harari, A. et al. An HIV-1 clade C DNA prime, NYVAC boost vaccine regimen induces reliable, polyfunctional, and long-lasting T cell responses. J. Exp. Med. 205, 63–77 (2008).
We are very grateful to B. Autran and P. Romero for helpful discussions and critical reading of this manuscript. We apologize to the authors of many excellent and relevant studies that we have been unable to cite owing to formatting constraints. D.A.P. is a Medical Research Council (UK) Senior Clinical Fellow.
About this article
Cite this article
Appay, V., Douek, D. & Price, D. CD8+ T cell efficacy in vaccination and disease. Nat Med 14, 623–628 (2008). https://doi.org/10.1038/nm.f.1774
This article is cited by
An organoid-based screen for epigenetic inhibitors that stimulate antigen presentation and potentiate T-cell-mediated cytotoxicity
Nature Biomedical Engineering (2021)
Nature Communications (2021)
Communications Biology (2021)
Journal of Experimental & Clinical Cancer Research (2020)
The armed oncolytic adenovirus ZD55-IL-24 eradicates melanoma by turning the tumor cells from the self-state into the nonself-state besides direct killing
Cell Death & Disease (2020)