Transplantation · 2026
Suppression of Costimulation Blockade-Resistant Memory CD8+ T cell-Mediated Rejection by TIGIT Agonism.
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Hartigan Christina R, Martinez Catherine D, Wagener Maylene E, Bazzano Julia M R, Alexander Katie L, Ford Mandy L
Аннотация
BACKGROUND: Costimulation blockade-based immunosuppression with belatacept confers improved renal function compared with calcineurin inhibitors, but comes at a cost of increased incidence and severity of early acute rejection. Strategies to limit costimulation blockade-resistant immune cells are needed. We have previously shown that the coinhibitory receptor T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) is expressed on memory T-cell subsets associated with costimulation blockade-resistant rejection in humans. Here, we aimed to determine the functional impact of TIGIT agonism on donor-reactive memory T-cell responses in the presence of costimulation blockade in a murine model of transplantation.
METHODS: We used an experimental transplant model in which murine recipients possess donor-reactive CD8+ T cells before transplantation and were treated with either cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA-4Ig) alone or CTLA-4Ig in the presence of an agonistic anti-TIGIT antibody.
RESULTS: Results demonstrated that a significant prolongation in graft survival was observed in mice treated with CTLA-4Ig plus the TIGIT agonist compared with CTLA-4Ig alone. Furthermore, the number of graft-infiltrating donor-reactive CD8+ T cells was significantly decreased, and the number of splenic forkhead box P3+ CD4+ regulatory T cells was significantly increased, in animals treated with CTLA-4Ig + TIGIT agonist compared with CTLA-4Ig alone. Finally, CTLA-4Ig + TIGIT agonist treatment resulted in the suppression of inflammatory transcriptional programs within donor-reactive CD8+ memory T cells.
CONCLUSIONS: These data suggest that agonism of the TIGIT coinhibitory pathway may effectively inhibit costimulation blockade-resistant memory T-cell responses.
METHODS: We used an experimental transplant model in which murine recipients possess donor-reactive CD8+ T cells before transplantation and were treated with either cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA-4Ig) alone or CTLA-4Ig in the presence of an agonistic anti-TIGIT antibody.
RESULTS: Results demonstrated that a significant prolongation in graft survival was observed in mice treated with CTLA-4Ig plus the TIGIT agonist compared with CTLA-4Ig alone. Furthermore, the number of graft-infiltrating donor-reactive CD8+ T cells was significantly decreased, and the number of splenic forkhead box P3+ CD4+ regulatory T cells was significantly increased, in animals treated with CTLA-4Ig + TIGIT agonist compared with CTLA-4Ig alone. Finally, CTLA-4Ig + TIGIT agonist treatment resulted in the suppression of inflammatory transcriptional programs within donor-reactive CD8+ memory T cells.
CONCLUSIONS: These data suggest that agonism of the TIGIT coinhibitory pathway may effectively inhibit costimulation blockade-resistant memory T-cell responses.