Why the study?
Despite their critical role in transplant rejection, a systematic study of allo-reactive memory T cells, their specificities, and the role of cross-reactivity with viral antigens had not been performed.
Prior viral infection generates cross-reactive memory CD8+ T cells that recognize alloantigens and promote rapid rejection of heart allografts in a mouse model.
Prior viral infection may accelerate cardiac allograft rejection via cross-reactive memory CD8+ T cells in mice; hypothesis-generating for heterologous immunity in clinical transplantation.
Introduction Significant evidence suggests a connection between transplant rejection and the presence of high levels of pre-existing memory T cells. Viral infection can elicit viral-specific memory T cells that cross-react with allo-MHC capable of driving allograft rejection in mice. Despite these advances, and despite their critical role in transplant rejection, a systematic study of allo-reactive memory T cells, their specificities, and the role of cross-reactivity with viral antigens has not been performed. Methods Here, we established a model to identify, isolate, and characterize cross-reactive T cells using Nur77 reporter mice (C57BL/6 background), which transiently express GFP exclusively upon TCR engagement. We infected Nur77 mice with lymphocytic choriomeningitis virus (LCMV-Armstrong) to generate a robust memory compartment, where quiescent LCMV-specific memory CD8 + T cells could be readily tracked with MHC tetramer staining. Then, we transplanted LCMV immune mice with allogeneic hearts and monitored expression of GFP within MHC-tetramer defined viral-specific T cells as an indicator of their ability to cross-react with alloantigens. Results Strikingly, prior LCMV infection significantly increased the kinetics and magnitude of rejection as well as CD8 + T cell recruitment into allogeneic, but not syngeneic, transplanted hearts, relative to non-infected controls. Interestingly, as early as day 1 after allogeneic heart transplant an average of ~8% of MHC-tetramer + CD8 + T cells expressed GFP, in contrast to syngeneic heart transplants, where the frequency of viral-specific CD8 + T cells that were GFP + was <1%. These data show that a significant percentage of viral-specific memory CD8 + T cells expressed T cell receptors that also recognized alloantigens in vivo . Notably, the frequency of cross-reactive CD8 + T cells differed depending upon the viral epitope. Further, TCR sequences derived from cross-reactive T cells harbored distinctive motifs that may provide insight into cross-reactivity and allo-specificity. Discussion In sum, we have established a mouse model to track viral-specific, allo-specific, and cross-reactive T cells; revealing that prior infection elicits substantial numbers of viral-specific T cells that cross-react to alloantigen, respond very early after transplant, and may promote rapid rejection.
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Khorki et al. (2023) studied this question.
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