TIGIT regulates apoptosis of risky memory T cell subsets implicated in belatacept-resistant rejection.

ABSTRACT: Belatacept confers increased patient and graft survival in renal transplant recipients relative to calcineurin inhibitors, but is associated with an increased rate of acute rejection. Recent immunophenotypic studies comparing pretransplant T cell phenotypes of patients who reject versus those who remain stable on belatacept identified three potential "risky" memory T cell subsets that potentially underlie belatacept-resistant rejection: CD4⁺ CD28⁺ T_EM , CD8⁺ CD28^null , and CD4⁺ CD57⁺ PD1^- subsets. Here, we compared key phenotypic and functional aspects of these human memory T cell subsets, with the goal of identifying additional potential targets to modulate them. Results demonstrate that TIGIT, an increasingly well-appreciated immune checkpoint receptor, was expressed on all three risky memory T cell subsets in vitro and in vivo in the presence of belatacept. Coculture of human memory CD4⁺ and CD8⁺ T cells with an agonistic anti-TIGIT mAb significantly increased apoptotic cell death of all three risky memory T cell subsets. Mechanistically, TIGIT-mediated apoptosis of risky memory T cells was dependent on FOXP3⁺ Treg, suggesting that agonism of the TIGIT pathway increases FOXP3⁺ Treg suppression of human memory T cell populations. Overall, these data suggest that TIGIT agonism could represent a new therapeutic target to inhibit belatacept-resistant rejection during transplantation.

SUBMITTER: Sun H 

PROVIDER: S-EPMC8458514 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature