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.
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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M.L.F. has received speaking honoraria from Veloxis Pharmaceuticals and Sanofi. The other authors declare no competing interests.
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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