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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.

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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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