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Activation and regulation of alloreactive T cell immunity in solid organ transplantation

Abstract

Transplantation is the only curative treatment for patients with kidney failure but it poses unique immunological challenges that must be overcome to prevent allograft rejection and ensure long-term graft survival. Alloreactive T cells are important contributors to graft rejection, and a clearer understanding of the mechanisms by which these cells recognize donor antigens — through direct, indirect or semi-direct pathways — will facilitate their therapeutic targeting. Post-T cell priming rejection responses can also be modified by targeting pathways that regulate T cell trafficking, survival cytokines or innate immune activation. Moreover, the quantity and quality of donor-reactive memory T cells crucially shape alloimmune responses. Of note, many fundamental concepts in transplant immunology have been derived from models of infection. However, the programmed differentiation of allograft-specific T cell responses is probably distinct from that of pathogen-elicited responses, owing to the dearth of pathogen-derived innate immune activation in the transplantation setting. Understanding the fundamental (and potentially unique) immunological pathways that lead to allograft rejection is therefore a prerequisite for the rational development of therapeutics that promote transplantation tolerance.

Key points

  • Direct, indirect and semi-direct alloantigen presentation all have important and potentially distinct roles in priming effective alloimmune responses. Semi-direct presentation occurs when recipient dendritic cells acquire donor peptide–MHC complexes in graft-draining secondary lymphoid organs by capturing clusters of donor-derived extracellular vesicles.

  • Allospecific T cell responses encounter antigen and undergo programmed differentiation in secondary lymphoid organs but their effector response is fine-tuned by further antigen presentation within the graft.

  • Pre-existing alloreactive memory T cells represent a substantial challenge in transplantation given their low activation threshold and resistance to costimulatory blockade. Preclinical data show that pharmacological blockade of the IL-2 and IL-15 receptors might be useful as adjunctive immunosuppression to optimize costimulation blockade therapy after transplantation.

  • Innate–adaptive immunity crosstalk has an important role in transplant rejection, and these pathways might be a source of potential therapeutic targets.

  • Key differences in priming conditions can induce distinct differentiation programmes in graft-elicited versus microorganism-elicited T cell responses, including the differential expression and function of pathways involving mammalian target of rapamycin, interferon regulatory factor 4 and coronin 1.

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Fig. 1: Mechanisms of allorecognition at the priming stage.
Fig. 2: Pathways of allorecognition and therapeutic strategies.
Fig. 3: Post-priming alloantigen recognition in the graft and potential therapeutic strategies.
Fig. 4: T cell migration to the graft.
Fig. 5: Targeting the crosstalk between the innate and adaptive immune system.
Fig. 6: Targeting survival cytokines in a preclinical model.

References

  1. Singer, A., Munitz, T. I., Golding, H., Rosenberg, A. S. & Mizuochi, T. Recognition requirements for the activation, differentiation and function of T-helper cells specific for class I MHC alloantigens. Immunol. Rev. 98, 143–170 (1987).

    CAS  PubMed  Article  Google Scholar 

  2. Bolton, E. M., Armstrong, H. E., Briggs, J. D. & Bradley, J. A. Cellular requirements for first-set renal allograft rejection. Transpl. Proc. 19, 321–323 (1987).

    CAS  Google Scholar 

  3. Bolton, E. M., Gracie, J. A., Briggs, J. D., Kampinga, J. & Bradley, J. A. Cellular requirements for renal allograft rejection in the athymic nude rat. J. Exp. Med. 169, 1931–1946 (1989).

    CAS  PubMed  Article  Google Scholar 

  4. Ashwell, J. D., Chen, C. & Schwartz, R. H. High frequency and nonrandom distribution of alloreactivity in T cell clones selected for recognition of foreign antigen in association with self class II molecules. J. Immunol. 136, 389–395 (1986).

    CAS  PubMed  Google Scholar 

  5. Suchin, E. J. et al. Quantifying the frequency of alloreactive T cells in vivo: new answers to an old question. J. Immunol. 166, 973–981 (2001).

    CAS  PubMed  Article  Google Scholar 

  6. Sherman, L. A. & Chattopadhyay, S. The molecular basis of allorecognition. Annu. Rev. Immunol. 11, 385–402 (1993).

    CAS  PubMed  Article  Google Scholar 

  7. Talmage, D. W., Dart, G., Radovich, J. & Lafferty, K. J. Activation of transplant immunity: effect of donor leukocytes on thyroid allograft rejection. Science 191, 385–388 (1976).

    CAS  PubMed  Article  Google Scholar 

  8. Lechler, R. I. & Batchelor, J. R. Restoration of immunogenicity to passenger cell-depleted kidney allografts by the addition of donor strain dendritic cells. J. Exp. Med. 155, 31–41 (1982).

    CAS  PubMed  Article  Google Scholar 

  9. Pietra, B. A., Wiseman, A., Bolwerk, A., Rizeq, M. & Gill, R. G. CD4 T cell-mediated cardiac allograft rejection requires donor but not host MHC class II. J. Clin. Invest. 106, 1003–1010 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. Larsen, C. P., Morris, P. J. & Austyn, J. M. Migration of dendritic leukocytes from cardiac allografts into host spleens. A novel pathway for initiation of rejection. J. Exp. Med. 171, 307–314 (1990).

    CAS  PubMed  Article  Google Scholar 

  11. Oluwole, S. et al. Donor pretreatment: rat heart allograft survival and measurement of passenger leukocyte depletion with indium-111. Transplantation 30, 31–33 (1980).

    CAS  PubMed  Article  Google Scholar 

  12. Tai, H. C. et al. Attempted depletion of passenger leukocytes by irradiation in pigs. J. Transpl. 2011, 928759 (2011).

    Google Scholar 

  13. Abrahimi, P. et al. Blocking MHC class II on human endothelium mitigates acute rejection. JCI Insight 1, e85293 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  14. Savage, C. O., Hughes, C. C., McIntyre, B. W., Picard, J. K. & Pober, J. S. Human CD4+ T cells proliferate to HLA-DR+ allogeneic vascular endothelium. Identification of accessory interactions. Transplantation 56, 128–134 (1993).

    CAS  PubMed  Article  Google Scholar 

  15. Grau, V., Herbst, B. & Steiniger, B. Dynamics of monocytes/macrophages and T lymphocytes in acutely rejecting rat renal allografts. Cell Tissue Res. 291, 117–126 (1998).

    CAS  PubMed  Article  Google Scholar 

  16. Penfield, J. G. et al. Transplant surgery injury recruits recipient MHC class II-positive leukocytes into the kidney. Kidney Int. 56, 1759–1769 (1999).

    CAS  PubMed  Article  Google Scholar 

  17. Saiki, T., Ezaki, T., Ogawa, M. & Matsuno, K. Trafficking of host- and donor-derived dendritic cells in rat cardiac transplantation: allosensitization in the spleen and hepatic nodes. Transplantation 71, 1806–1815 (2001).

    CAS  PubMed  Article  Google Scholar 

  18. Celli, S., Albert, M. L. & Bousso, P. Visualizing the innate and adaptive immune responses underlying allograft rejection by two-photon microscopy. Nat. Med. 17, 744–749 (2011).

    CAS  PubMed  Article  Google Scholar 

  19. Benichou, G., Takizawa, P. A., Olson, C. A., McMillan, M. & Sercarz, E. E. Donor major histocompatibility complex (MHC) peptides are presented by recipient MHC molecules during graft rejection. J. Exp. Med. 175, 305–308 (1992).

    CAS  PubMed  Article  Google Scholar 

  20. Benichou, G. et al. Limited T cell response to donor MHC peptides during allograft rejection. Implications for selective immune therapy in transplantation. J. Immunol. 153, 938–945 (1994).

    CAS  PubMed  Google Scholar 

  21. Gallon, L. et al. The indirect pathway of allorecognition. The occurrence of self-restricted T cell recognition of allo-MHC peptides early in acute renal allograft rejection and its inhibition by conventional immunosuppression. Transplantation 59, 612–616 (1995).

    CAS  PubMed  Article  Google Scholar 

  22. Harris, P. E., Cortesini, R. & Suciu-Foca, N. Indirect allorecognition in solid organ transplantation. Rev. Immunogenet. 1, 297–308 (1999).

    CAS  PubMed  Google Scholar 

  23. Gould, D. S. & Auchincloss, H. Direct and indirect recognition: the role of MHC antigens in graft rejection. Immunol. Today 20, 77–82 (1999).

    CAS  PubMed  Article  Google Scholar 

  24. Ali, J. M., Bolton, E. M., Bradley, J. A. & Pettigrew, G. J. Allorecognition pathways in transplant rejection and tolerance. Transplantation 96, 681–688 (2013).

    CAS  PubMed  Article  Google Scholar 

  25. Baker, R. J. et al. Loss of direct and maintenance of indirect alloresponses in renal allograft recipients: implications for the pathogenesis of chronic allograft nephropathy. J. Immunol. 167, 7199–7206 (2001).

    CAS  PubMed  Article  Google Scholar 

  26. Haynes, L. D. et al. Donor-specific indirect pathway analysis reveals a B-cell-independent signature which reflects outcomes in kidney transplant recipients. Am. J. Transpl. 12, 640–648 (2012).

    CAS  Article  Google Scholar 

  27. Ali, J. M. et al. Diversity of the CD4 T cell alloresponse: the short and the long of it. Cell Rep. 14, 1232–1245 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. Kreisel, D. et al. Vascular endothelium does not activate CD4+ direct allorecognition in graft rejection. J. Immunol. 173, 3027–3034 (2004).

    CAS  PubMed  Article  Google Scholar 

  29. Hackstein, H. et al. Rapamycin inhibits IL-4-induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo. Blood 101, 4457–4463 (2003).

    CAS  PubMed  Article  Google Scholar 

  30. Taner, T., Hackstein, H., Wang, Z., Morelli, A. E. & Thomson, A. W. Rapamycin-treated, alloantigen-pulsed host dendritic cells induce Ag-specific T cell regulation and prolong graft survival. Am. J. Transpl. 5, 228–236 (2005).

    CAS  Article  Google Scholar 

  31. Fischer, R. T., Turnquist, H. R., Wang, Z., Beer-Stolz, D. & Thomson, A. W. Rapamycin-conditioned, alloantigen-pulsed myeloid dendritic cells present donor MHC class I/peptide via the semi-direct pathway and inhibit survival of antigen-specific CD8+ T cells in vitro and in vivo. Transpl. Immunol. 25, 20–26 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. Liu, Q. et al. Donor dendritic cell-derived exosomes promote allograft-targeting immune response. J. Clin. Invest. 126, 2805–2820 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  33. Marino, J. et al. Donor exosomes rather than passenger leukocytes initiate alloreactive T cell responses after transplantation. Sci. Immunol. 1, aaf8759 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  34. Russo, V. et al. Acquisition of intact allogeneic human leukocyte antigen molecules by human dendritic cells. Blood 95, 3473–3477 (2000).

    CAS  PubMed  Article  Google Scholar 

  35. Joly, E. & Hudrisier, D. What is trogocytosis and what is its purpose? Nat. Immunol. 4, 815 (2003).

    CAS  PubMed  Article  Google Scholar 

  36. Knight, S. C., Iqball, S., Roberts, M. S., Macatonia, S. & Bedford, P. A. Transfer of antigen between dendritic cells in the stimulation of primary T cell proliferation. Eur. J. Immunol. 28, 1636–1644 (1998).

    CAS  PubMed  Article  Google Scholar 

  37. Wykes, M., Pombo, A., Jenkins, C. & MacPherson, G. G. Dendritic cells interact directly with naive B lymphocytes to transfer antigen and initiate class switching in a primary T-dependent response. J. Immunol. 161, 1313–1319 (1998).

    CAS  PubMed  Google Scholar 

  38. Herrera, O. B. et al. A novel pathway of alloantigen presentation by dendritic cells. J. Immunol. 173, 4828–4837 (2004).

    CAS  PubMed  Article  Google Scholar 

  39. Benichou, G., Wang, M., Ahrens, K. & Madsen, J. C. Extracellular vesicles in allograft rejection and tolerance. Cell Immunol. 349, 104063 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Harper, S. J. et al. CD8 T-cell recognition of acquired alloantigen promotes acute allograft rejection. Proc. Natl Acad. Sci. USA 112, 12788–12793 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. Brown, K., Sacks, S. H. & Wong, W. Extensive and bidirectional transfer of major histocompatibility complex class II molecules between donor and recipient cells in vivo following solid organ transplantation. FASEB J. 22, 3776–3784 (2008).

    CAS  PubMed  Article  Google Scholar 

  42. Brown, K., Sacks, S. H. & Wong, W. Coexpression of donor peptide/recipient MHC complex and intact donor MHC: evidence for a link between the direct and indirect pathways. Am. J. Transpl. 11, 826–831 (2011).

    CAS  Article  Google Scholar 

  43. Sivaganesh, S. et al. Copresentation of intact and processed MHC alloantigen by recipient dendritic cells enables delivery of linked help to alloreactive CD8 T cells by indirect-pathway CD4 T cells. J. Immunol. 190, 5829–5838 (2013).

    CAS  PubMed  Article  Google Scholar 

  44. Smyth, L. A., Lechler, R. I. & Lombardi, G. Continuous acquisition of MHC:peptide complexes by recipient cells contributes to the generation of anti-graft CD8+ T cell immunity. Am. J. Transpl. 17, 60–68 (2017).

    CAS  Article  Google Scholar 

  45. Frängsmyr, L. et al. Cytoplasmic microvesicular form of Fas ligand in human early placenta: switching the tissue immune privilege hypothesis from cellular to vesicular level. Mol. Hum. Reprod. 11, 35–41 (2005).

    PubMed  Article  CAS  Google Scholar 

  46. LeMaoult, J. et al. Immune regulation by pretenders: cell-to-cell transfers of HLA-G make effector T cells act as regulatory cells. Blood 109, 2040–2048 (2007).

    CAS  PubMed  Article  Google Scholar 

  47. Brown, R. et al. CD86+ or HLA-G+ can be transferred via trogocytosis from myeloma cells to T cells and are associated with poor prognosis. Blood 120, 2055–2063 (2012).

    CAS  PubMed  Article  Google Scholar 

  48. Caumartin, J. et al. Trogocytosis-based generation of suppressive NK cells. EMBO J. 26, 1423–1433 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. HoWangYin, K. Y. et al. Proper regrafting of Ig-like transcript 2 after trogocytosis allows a functional cell-cell transfer of sensitivity. J. Immunol. 186, 2210–2218 (2011).

    CAS  PubMed  Article  Google Scholar 

  50. Tilburgs, T., Evans, J. H., Crespo, Â. & Strominger, J. L. The HLA-G cycle provides for both NK tolerance and immunity at the maternal-fetal interface. Proc. Natl Acad. Sci. USA 112, 13312–13317 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. Ono, Y. et al. Graft-infiltrating PD-L1. Hepatology 67, 1499–1515 (2018).

    CAS  PubMed  Article  Google Scholar 

  52. Sigdel, T. K. et al. Perturbations in the urinary exosome in transplant rejection. Front. Med. 1, 57 (2014).

    Google Scholar 

  53. Lim, J. H. et al. Novel urinary exosomal biomarkers of acute T cell-mediated rejection in kidney transplant recipients: a cross-sectional study. PLoS ONE 13, e0204204 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  54. Tower, C. M. et al. Plasma C4d+ endothelial microvesicles increase in acute antibody-mediated rejection. Transplantation 101, 2235–2243 (2017).

    CAS  PubMed  Article  Google Scholar 

  55. Zhang, H. et al. Plasma exosomes from HLA-sensitized kidney transplant recipients contain mRNA transcripts which predict development of antibody-mediated rejection. Transplantation 101, 2419–2428 (2017).

    CAS  PubMed  Article  Google Scholar 

  56. Park, J. et al. Integrated kidney exosome analysis for the detection of kidney transplant rejection. ACS Nano 11, 11041–11046 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. Racusen, L. C. et al. The Banff 97 working classification of renal allograft pathology. Kidney Int. 55, 713–723 (1999).

    CAS  PubMed  Article  Google Scholar 

  58. Pêche, H., Heslan, M., Usal, C., Amigorena, S. & Cuturi, M. C. Presentation of donor major histocompatibility complex antigens by bone marrow dendritic cell-derived exosomes modulates allograft rejection. Transplantation 76, 1503–1510 (2003).

    PubMed  Article  CAS  Google Scholar 

  59. Ma, B. et al. Combining exosomes derived from immature DCs with donor antigen-specific Treg cells induces tolerance in a rat liver allograft model. Sci. Rep. 6, 32971 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Halloran, P. F., Einecke, G., Sikosana, M. L. N. & Madill-Thomsen, K. in Pharmacology of Immunosuppression. Handbook of Experimental Pharmacology Vol. 272 (ed. Eisen, H. J) 1–26 (Springer, 2021).

  61. Hidalgo, L. G. et al. The transcriptome of human cytotoxic T cells: measuring the burden of CTL-associated transcripts in human kidney transplants. Am. J. Transpl. 8, 637–646 (2008).

    CAS  Article  Google Scholar 

  62. Einecke, G. et al. Expression of CTL associated transcripts precedes the development of tubulitis in T-cell mediated kidney graft rejection. Am. J. Transpl. 5, 1827–1836 (2005).

    CAS  Article  Google Scholar 

  63. Zhuang, Q. et al. Graft-infiltrating host dendritic cells play a key role in organ transplant rejection. Nat. Commun. 7, 12623 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Tacke, F. et al. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J. Clin. Invest. 117, 185–194 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. Serbina, N. V., Salazar-Mather, T. P., Biron, C. A., Kuziel, W. A. & Pamer, E. G. TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity 19, 59–70 (2003).

    CAS  PubMed  Article  Google Scholar 

  66. Aldridge, J. R. et al. TNF/iNOS-producing dendritic cells are the necessary evil of lethal influenza virus infection. Proc. Natl Acad. Sci. USA 106, 5306–5311 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. De Trez, C. et al. iNOS-producing inflammatory dendritic cells constitute the major infected cell type during the chronic Leishmania major infection phase of C57BL/6 resistant mice. PLoS Pathog. 5, e1000494 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  68. D’Elios, M. M. et al. Predominant Th1 cell infiltration in acute rejection episodes of human kidney grafts. Kidney Int. 51, 1876–1884 (1997).

    PubMed  Article  Google Scholar 

  69. Li, J. et al. The evolving roles of macrophages in organ transplantation. J. Immunol. Res. 2019, 5763430 (2019).

    PubMed  PubMed Central  Google Scholar 

  70. van den Bosch, T. P., Kannegieter, N. M., Hesselink, D. A., Baan, C. C. & Rowshani, A. T. Targeting the monocyte-macrophage lineage in solid organ transplantation. Front. Immunol. 8, 153 (2017).

    PubMed  PubMed Central  Google Scholar 

  71. Adams, A. B. et al. Heterologous immunity provides a potent barrier to transplantation tolerance. J. Clin. Invest. 111, 1887–1895 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. Adams, A. B., Pearson, T. C. & Larsen, C. P. Heterologous immunity: an overlooked barrier to tolerance. Immunol. Rev. 196, 147–160 (2003).

    CAS  PubMed  Article  Google Scholar 

  73. Jameson, S. C. & Masopust, D. Diversity in T cell memory: an embarrassment of riches. Immunity 31, 859–871 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. Croft, M., Bradley, L. M. & Swain, S. L. Naive versus memory CD4 T cell response to antigen. Memory cells are less dependent on accessory cell costimulation and can respond to many antigen-presenting cell types including resting B cells. J. Immunol. 152, 2675–2685 (1994).

    CAS  PubMed  Google Scholar 

  75. Walch, J. M. et al. Cognate antigen directs CD8+ T cell migration to vascularized transplants. J. Clin. Invest. 123, 2663–2671 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. Benichou, G., Gonzalez, B., Marino, J., Ayasoufi, K. & Valujskikh, A. Role of memory T cells in allograft rejection and tolerance. Front. Immunol. 8, 170 (2017).

    PubMed  PubMed Central  Google Scholar 

  77. Chen, Y., Heeger, P. S. & Valujskikh, A. In vivo helper functions of alloreactive memory CD4+ T cells remain intact despite donor-specific transfusion and anti-CD40 ligand therapy. J. Immunol. 172, 5456–5466 (2004).

    CAS  PubMed  Article  Google Scholar 

  78. Valujskikh, A., Pantenburg, B. & Heeger, P. S. Primed allospecific T cells prevent the effects of costimulatory blockade on prolonged cardiac allograft survival in mice. Am. J. Transpl. 2, 501–509 (2002).

    CAS  Article  Google Scholar 

  79. Welsh, R. M. et al. Virus-induced abrogation of transplantation tolerance induced by donor-specific transfusion and anti-CD154 antibody. J. Virol. 74, 2210–2218 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. Zhai, Y., Meng, L., Gao, F., Busuttil, R. W. & Kupiec-Weglinski, J. W. Allograft rejection by primed/memory CD8+ T cells is CD154 blockade resistant: therapeutic implications for sensitized transplant recipients. J. Immunol. 169, 4667–4673 (2002).

    CAS  PubMed  Article  Google Scholar 

  81. Krummey, S. M. & Ford, M. L. Heterogeneity within T cell memory: implications for transplant tolerance. Front. Immunol. 3, 36 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. Krummey, S. M. & Ford, M. L. New insights into T-cell cosignaling in allograft rejection and survival. Curr. Opin. Organ. Transpl. 20, 43–48 (2015).

    CAS  Article  Google Scholar 

  83. Mathews, D. V. et al. CD122 signaling in CD8+ memory T cells drives costimulation-independent rejection. J. Clin. Invest. 128, 4557–4572 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  84. Hartigan, C. R., Sun, H. & Ford, M. L. Memory T-cell exhaustion and tolerance in transplantation. Immunol. Rev. 292, 225–242 (2019).

    CAS  PubMed  Article  Google Scholar 

  85. Shapira, M. Y. et al. Rapid response to alefacept given to patients with steroid resistant or steroid dependent acute graft-versus-host disease: a preliminary report. Bone Marrow Transpl. 36, 1097–1101 (2005).

    CAS  Article  Google Scholar 

  86. Shapira, M. Y. et al. A new induction protocol for the control of steroid refractory/dependent acute graft versus host disease with alefacept and tacrolimus. Cytotherapy 11, 61–67 (2009).

    CAS  PubMed  Article  Google Scholar 

  87. Shapira, M. Y. et al. Alefacept treatment for refractory chronic extensive GVHD. Bone Marrow Transpl. 43, 339–343 (2009).

    CAS  Article  Google Scholar 

  88. Lo, D. J. et al. Selective targeting of human alloresponsive CD8+ effector memory T cells based on CD2 expression. Am. J. Transpl. 11, 22–33 (2011).

    CAS  Article  Google Scholar 

  89. Weaver, T. A. et al. Alefacept promotes co-stimulation blockade based allograft survival in nonhuman primates. Nat. Med. 15, 746–749 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. Kitchens, W. H., Larsen, C. P. & Ford, M. L. Integrin antagonists for transplant immunosuppression: panacea or peril. Immunotherapy 3, 305–307 (2011).

    PubMed  Article  Google Scholar 

  91. Kitchens, W. H. et al. Integrin antagonists prevent costimulatory blockade-resistant transplant rejection by CD8+ memory T cells. Am. J. Transpl. 12, 69–80 (2012).

    CAS  Article  Google Scholar 

  92. Setoguchi, K. et al. LFA-1 antagonism inhibits early infiltration of endogenous memory CD8 T cells into cardiac allografts and donor-reactive T cell priming. Am. J. Transpl. 11, 923–935 (2011).

    CAS  Article  Google Scholar 

  93. Iida, S. et al. Peritransplant VLA-4 blockade inhibits endogenous memory CD8 T cell infiltration into high-risk cardiac allografts and CTLA-4Ig resistant rejection. Am. J. Transpl. 19, 998–1010 (2019).

    CAS  Article  Google Scholar 

  94. Turgeon, N. A. et al. Experience with a novel efalizumab-based immunosuppressive regimen to facilitate single donor islet cell transplantation. Am. J. Transpl. 10, 2082–2091 (2010).

    CAS  Article  Google Scholar 

  95. Posselt, A. M. et al. Islet transplantation in type 1 diabetics using an immunosuppressive protocol based on the anti-LFA-1 antibody efalizumab. Am. J. Transpl. 10, 1870–1880 (2010).

    CAS  Article  Google Scholar 

  96. Vincenti, F. et al. A phase I/II randomized open-label multicenter trial of efalizumab, a humanized anti-CD11a, anti-LFA-1 in renal transplantation. Am. J. Transpl. 7, 1770–1777 (2007).

    CAS  Article  Google Scholar 

  97. Carson, K. R. et al. Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: a review from the research on adverse drug events and reports (RADAR) project. Lancet Oncol. 10, 816–824 (2009).

    CAS  PubMed  Article  Google Scholar 

  98. Kirk, A. D. et al. Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates. Nat. Med. 5, 686–693 (1999).

    CAS  PubMed  Article  Google Scholar 

  99. Larsen, C. P. et al. Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways. Nature 381, 434–438 (1996).

    CAS  PubMed  Article  Google Scholar 

  100. Liu, D. & Ford, M. L. CD11b is a novel alternate receptor for CD154 during alloimmunity. Am. J. Transpl. 20, 2216–2225 (2020).

    CAS  Article  Google Scholar 

  101. Wolf, D. et al. Binding of CD40L to Mac-1’s I-domain involves the EQLKKSKTL motif and mediates leukocyte recruitment and atherosclerosis — but does not affect immunity and thrombosis in mice. Circ. Res. 109, 1269–1279 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. Michel, N. A., Zirlik, A. & Wolf, D. CD40L and its receptors in atherothrombosis — an update. Front. Cardiovasc. Med. 4, 40 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  103. Hancock, W. W., Gao, W., Faia, K. L. & Csizmadia, V. Chemokines and their receptors in allograft rejection. Curr. Opin. Immunol. 12, 511–516 (2000).

    CAS  PubMed  Article  Google Scholar 

  104. Halloran, P. F. & Fairchild, R. L. The puzzling role of CXCR3 and its ligands in organ allograft rejection. Am. J. Transpl. 8, 1578–1579 (2008).

    CAS  Article  Google Scholar 

  105. Oberbarnscheidt, M. H. et al. Memory T cells migrate to and reject vascularized cardiac allografts independent of the chemokine receptor CXCR3. Transplantation 91, 827–832 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. Hoffmann, S. C. et al. Molecular and immunohistochemical characterization of the onset and resolution of human renal allograft ischemia-reperfusion injury. Transplantation 74, 916–923 (2002).

    CAS  PubMed  Article  Google Scholar 

  107. Mori, D. N., Kreisel, D., Fullerton, J. N., Gilroy, D. W. & Goldstein, D. R. Inflammatory triggers of acute rejection of organ allografts. Immunol. Rev. 258, 132–144 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  108. Ponticelli, C. Ischaemia-reperfusion injury: a major protagonist in kidney transplantation. Nephrol. Dial. Transpl. 29, 1134–1140 (2014).

    CAS  Article  Google Scholar 

  109. Pandey, S., Kawai, T. & Akira, S. Microbial sensing by Toll-like receptors and intracellular nucleic acid sensors. Cold Spring Harb. Perspect. Biol. 7, a016246 (2014).

    PubMed  Article  CAS  Google Scholar 

  110. Goldstein, D. R., Tesar, B. M., Akira, S. & Lakkis, F. G. Critical role of the Toll-like receptor signal adaptor protein MyD88 in acute allograft rejection. J. Clin. Invest. 111, 1571–1578 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. Messmer, D. et al. High mobility group box protein 1: an endogenous signal for dendritic cell maturation and Th1 polarization. J. Immunol. 173, 307–313 (2004).

    CAS  PubMed  Article  Google Scholar 

  112. McNulty, S. et al. Heat-shock proteins as dendritic cell-targeting vaccines — getting warmer. Immunology 139, 407–415 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. Tesar, B. M. et al. The role of hyaluronan degradation products as innate alloimmune agonists. Am. J. Transpl. 6, 2622–2635 (2006).

    CAS  Article  Google Scholar 

  114. Braudeau, C. et al. Contrasted blood and intragraft Toll-like receptor 4 mRNA profiles in operational tolerance versus chronic rejection in kidney transplant recipients. Transplantation 86, 130–136 (2008).

    CAS  PubMed  Article  Google Scholar 

  115. Sharbafi, M. H. et al. TLR-2, TLR-4 and MyD88 genes expression in renal transplant acute and chronic rejections. Int. J. Immunogenet. 46, 427–436 (2019).

    CAS  PubMed  Article  Google Scholar 

  116. Deng, J. F. et al. The role of Toll-like receptors 2 and 4 in acute allograft rejection after liver transplantation. Transpl. Proc. 39, 3222–3224 (2007).

    CAS  Article  Google Scholar 

  117. Braza, F., Brouard, S., Chadban, S. & Goldstein, D. R. Role of TLRs and DAMPs in allograft inflammation and transplant outcomes. Nat. Rev. Nephrol. 12, 281–290 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. Kulkarni, H. S., Scozzi, D. & Gelman, A. E. Recent advances into the role of pattern recognition receptors in transplantation. Cell Immunol. 351, 104088 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT01794663 (2017).

  120. US National Library of Medicine. ClinicalTrials.gov https://ClinicalTrials.gov/show/NCT01808469 (2014).

  121. Biglarnia, A. R., Huber-Lang, M., Mohlin, C., Ekdahl, K. N. & Nilsson, B. The multifaceted role of complement in kidney transplantation. Nat. Rev. Nephrol. 14, 767–781 (2018).

    CAS  PubMed  Article  Google Scholar 

  122. Mathern, D. R. & Heeger, P. S. Molecules great and small: the complement system. Clin. J. Am. Soc. Nephrol. 10, 1636–1650 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. Lalli, P. N. et al. Locally produced C5a binds to T cell-expressed C5aR to enhance effector T-cell expansion by limiting antigen-induced apoptosis. Blood 112, 1759–1766 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. Strainic, M. G. et al. Locally produced complement fragments C5a and C3a provide both costimulatory and survival signals to naive CD4+ T cells. Immunity 28, 425–435 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. Sheen, J. H. et al. TLR-induced murine dendritic cell (DC) activation requires DC-intrinsic complement. J. Immunol. 199, 278–291 (2017).

    CAS  PubMed  Article  Google Scholar 

  126. Arbore, G. et al. T helper 1 immunity requires complement-driven NLRP3 inflammasome activity in CD4+ T cells. Science 352, aad1210 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  127. Mathern, D. R., K Horwitz, J. & Heeger, P. S. Absence of recipient C3aR1 signaling limits expansion and differentiation of alloreactive CD8+ T cell immunity and prolongs murine cardiac allograft survival. Am. J. Transpl. 19, 1628–1640 (2019).

    CAS  Article  Google Scholar 

  128. Kwan, W. H., van der Touw, W., Paz-Artal, E., Li, M. O. & Heeger, P. S. Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells. J. Exp. Med. 210, 257–268 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. Strainic, M. G., Shevach, E. M., An, F., Lin, F. & Medof, M. E. Absence of signaling into CD4+ cells via C3aR and C5aR enables autoinductive TGF-β1 signaling and induction of Foxp3+ regulatory T cells. Nat. Immunol. 14, 162–171 (2013).

    CAS  PubMed  Article  Google Scholar 

  130. van der Touw, W. et al. Cutting edge: receptors for C3a and C5a modulate stability of alloantigen-reactive induced regulatory T cells. J. Immunol. 190, 5921–5925 (2013).

    PubMed  Article  CAS  Google Scholar 

  131. Ono, M., Bolland, S., Tempst, P. & Ravetch, J. V. Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor FcγRIIB. Nature 383, 263–266 (1996).

    CAS  PubMed  Article  Google Scholar 

  132. Nimmerjahn, F. & Ravetch, J. V. Fcγ receptors as regulators of immune responses. Nat. Rev. Immunol. 8, 34–47 (2008).

    CAS  PubMed  Article  Google Scholar 

  133. Wirth, T. C. et al. Repetitive antigen stimulation induces stepwise transcriptome diversification but preserves a core signature of memory CD8+ T cell differentiation. Immunity 33, 128–140 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. Starbeck-Miller, G. R., Badovinac, V. P., Barber, D. L. & Harty, J. T. Cutting edge: expression of FcγRIIB tempers memory CD8 T cell function in vivo. J. Immunol. 192, 35–39 (2014).

    CAS  PubMed  Article  Google Scholar 

  135. Alfei, F. et al. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature 571, 265–269 (2019).

    CAS  PubMed  Article  Google Scholar 

  136. Morris, A. B. et al. Signaling through the inhibitory Fc receptor FcγRIIB induces CD8. Immunity 52, 136–150.e6 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. Liu, H. et al. The FGL2-FcγRIIB pathway: a novel mechanism leading to immunosuppression. Eur. J. Immunol. 38, 3114–3126 (2008).

    CAS  PubMed  Article  Google Scholar 

  138. Hricik, D. E. et al. Adverse outcomes of tacrolimus withdrawal in immune-quiescent kidney transplant recipients. J. Am. Soc. Nephrol. 26, 3114–3122 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. Hu, J. et al. The duality of Fgl2-secreted immune checkpoint regulator versus membrane-associated procoagulant: therapeutic potential and implications. Int. Rev. Immunol. 35, 325–339 (2016).

    CAS  PubMed  Google Scholar 

  140. Joller, N. et al. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity 40, 569–581 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. Amir, A. L. et al. Allo-HLA reactivity of virus-specific memory T cells is common. Blood 115, 3146–3157 (2010).

    CAS  PubMed  Article  Google Scholar 

  142. Nadazdin, O. et al. Host alloreactive memory T cells influence tolerance to kidney allografts in nonhuman primates. Sci. Transl Med. 3, 86ra51 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  143. Bozeman, A. M., Laurie, S. J., Haridas, D., Wagener, M. E. & Ford, M. L. Transplantation preferentially induces a KLRG-1lo CD127hi differentiation program in antigen-specific CD8+ T cells. Transpl. Immunol. 50, 34–42 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. Burrows, S. R. et al. T cell receptor repertoire for a viral epitope in humans is diversified by tolerance to a background major histocompatibility complex antigen. J. Exp. Med. 182, 1703–1715 (1995).

    CAS  PubMed  Article  Google Scholar 

  145. Barton, E., Mandal, P. & Speck, S. H. Pathogenesis and host control of gammaherpesviruses: lessons from the mouse. Annu. Rev. Immunol. 29, 351–397 (2011).

    CAS  PubMed  Article  Google Scholar 

  146. Larsen, C. P. et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am. J. Transpl. 5, 443–453 (2005).

    CAS  Article  Google Scholar 

  147. Floyd, T. L. et al. Limiting the amount and duration of antigen exposure during priming increases memory T cell requirement for costimulation during recall. J. Immunol. 186, 2033–2041 (2011).

    CAS  PubMed  Article  Google Scholar 

  148. Traitanon, O. et al. IL-15 induces alloreactive CD28 memory CD8 T cell proliferation and CTLA4-Ig resistant memory CD8 T cell activation. Am. J. Transpl. 14, 1277–1289 (2014).

    CAS  Article  Google Scholar 

  149. Asderakis, A. et al. Thymoglobulin versus alemtuzumab versus basiliximab kidney transplantation from donors after circulatory death. Kidney Int. Rep. 7, 732–740 (2022).

    PubMed  PubMed Central  Article  Google Scholar 

  150. Xie, C. B. et al. Complement-activated interferon-gamma-primed human endothelium transpresents interleukin-15 to CD8+ T cells. J. Clin. Invest. 130, 3437–3452 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  151. Ferrer, I. R., Araki, K. & Ford, M. L. Paradoxical aspects of rapamycin immunobiology in transplantation. Am. J. Transpl. 11, 654–659 (2011).

    CAS  Article  Google Scholar 

  152. Turner, A. P. et al. Sirolimus enhances the magnitude and quality of viral-specific CD8+ T-cell responses to vaccinia virus vaccination in rhesus macaques. Am. J. Transpl. 11, 613–618 (2011).

    CAS  Article  Google Scholar 

  153. Araki, K. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. Ferrer, I. R. et al. Cutting edge: rapamycin augments pathogen-specific but not graft-reactive CD8+ T cell responses. J. Immunol. 185, 2004–2008 (2010).

    CAS  PubMed  Article  Google Scholar 

  155. Föger, N., Rangell, L., Danilenko, D. M. & Chan, A. C. Requirement for coronin 1 in T lymphocyte trafficking and cellular homeostasis. Science 313, 839–842 (2006).

    PubMed  Article  CAS  Google Scholar 

  156. Mueller, P. et al. Regulation of T cell survival through coronin-1-mediated generation of inositol-1,4,5-trisphosphate and calcium mobilization after T cell receptor triggering. Nat. Immunol. 9, 424–431 (2008).

    CAS  PubMed  Article  Google Scholar 

  157. Shiow, L. R. et al. The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency. Nat. Immunol. 9, 1307–1315 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  158. Jayachandran, R. et al. Disruption of coronin 1 signaling in T cells promotes allograft tolerance while maintaining anti-pathogen immunity. Immunity 50, 152–165.e8 (2019).

    CAS  PubMed  Article  Google Scholar 

  159. Bourne, H. R. et al. Modulation of inflammation and immunity by cyclic AMP. Science 184, 19–28 (1974).

    CAS  PubMed  Article  Google Scholar 

  160. Bopp, T. et al. Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J. Exp. Med. 204, 1303–1310 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. Mosenden, R. & Taskén, K. Cyclic AMP-mediated immune regulation — overview of mechanisms of action in T cells. Cell. Signal. 23, 1009–1016 (2011).

    CAS  PubMed  Article  Google Scholar 

  162. Ford, M. L. Coronin-1, King of Alloimmunity. Immunity 50, 3–5 (2019).

    CAS  PubMed  Article  Google Scholar 

  163. Moshous, D. et al. Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation. J. Allergy Clin. Immunol. 131, 1594–1603 (2013).

    CAS  PubMed  Article  Google Scholar 

  164. Man, K. et al. Transcription factor IRF4 promotes CD8+ T cell exhaustion and limits the development of memory-like T cells during chronic infection. Immunity 47, 1129–1141.e5 (2017).

    CAS  PubMed  Article  Google Scholar 

  165. Wu, J. et al. Ablation of transcription factor IRF4 promotes transplant acceptance by driving allogenic CD4+ T cell dysfunction. Immunity 47, 1114–1128.e6 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  166. Liu, L. et al. Bortezomib ameliorates acute allograft rejection after renal transplant by inhibiting Tfh cell proliferation and differentiation via miR-15b/IRF4 axis. Int. Immunopharmacol. 75, 105758 (2019).

    CAS  PubMed  Article  Google Scholar 

  167. Epperson, D. E. & Pober, J. S. Antigen-presenting function of human endothelial cells. Direct activation of resting CD8 T cells. J. Immunol. 153, 5402–5412 (1994).

    CAS  PubMed  Google Scholar 

  168. Beura, L. K. et al. Normalizing the environment recapitulates adult human immune traits in laboratory mice. Nature 532, 512–516 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  169. Winterberg, P. D. & Ford, M. L. The effect of chronic kidney disease on T cell alloimmunity. Curr. Opin. Organ. Transpl. 22, 22–28 (2017).

    CAS  Article  Google Scholar 

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All authors researched data for the article, made substantial contributions to discussions of the content and reviewed or edited the manuscript before submission. C.D. and M.L.F. wrote the manuscript.

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Duneton, C., Winterberg, P.D. & Ford, M.L. Activation and regulation of alloreactive T cell immunity in solid organ transplantation. Nat Rev Nephrol 18, 663–676 (2022). https://doi.org/10.1038/s41581-022-00600-0

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