Regulation of alloreactive CD8+ memory T cells by tigit

The National Institute of Allergy and Infectious Diseases awarded Emory University $100,228 on September 30, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate the regulation of alloreactive CD8+ memory T cells by TIGIT in organ transplantation.

The research examines TIGIT agonism as a mechanism to reduce allograft rejection mediated by CD8+ memory T cell responses. Standard immunosuppressive therapies such as calcineurin inhibitors cause long-term allograft damage, while belatacept (a CTLA-4IG variant) improves kidney function but is associated with increased acute rejection rates. Preliminary data demonstrate that TIGIT agonism combined with CTLA-4IG improves allograft survival in a murine skin graft model by reducing CD8+ memory T cell infiltration in the allograft. The research aims to further evaluate the mechanism by which TIGIT agonism targets CD8+ memory T cells either directly or indirectly through regulatory T cells to improve allograft survival.

Performance occurs in Atlanta, Georgia, with a period of performance from September 30, 2026, through March 31, 2029. Emory University, a tax-exempt nonprofit research institution, serves as the prime recipient through its Office of Sponsored Programs Division.

Abstract

Transplantation serves as an effective remedy for end-stage organ failure. Standard-of-care treatment with calcineurin inhibitors (CNI) have successfully reduced immune-mediated allograft rejection, at the cost of damaging the allograft over time (i.e., nephrotoxicity). Belatacept (ctla-4IG variant) is associated with improved kidney function in renal transplant recipients. However, use of ctla-4IG was associated with increased rates of early acute rejection compared to CNI. CD8+ memory T cells are generally less reliant on costimulatory signaling for their activation and mount a more rapid and robust response. Therefore, the recipients' immunological memory may be a potential mediator of acute rejection. Several groups have identified subsets of memory T cells underlying belatacept-resistant rejection. We interrogated the phenotypes of these human memory T cells and identified the shared expression of a coinhibitory molecule T cell immunoreceptor with immunoglobulin domains (TIGIT), thus presenting TIGIT as a direct target on CD8+ memory T cell subsets. Numerous groups have used immunomodulatory agents as therapeutics for a range of pathologies (i.e., transplant, cancer, autoimmunity). As an example, the blockade of TIGIT and PD-1/L1 has shown promising results for the treatment of cancer. Here, we investigate the ability of TIGIT agonism to minimize allograft rejection mediated by the recipient's immunological memory. Our preliminary data show that TIGIT agonism plus ctla-4IG improves allograft survival in a murine skin graft model of naïve and memory CD8+ T cells. The addition of TIGIT agonism is accompanied with a reduction in the numbers of CD8+ memory T cells in the allograft of both models. These data highlight the ability of TIGIT agonism to target CD8+ memory T cells either directly or indirectly by tregs to improve allograft survival. We aim to further evaluate the mechanisms underlying the survival benefit employed by TIGIT agonism using murine skin graft models. We believe TIGIT agonism may hold promise as an adjunct immunotherapy to attenuate CD8+ memory T cell mediated costimulation-blockade resistant rejection. With reduced immunosuppression induced toxicities and reduced rates of acute rejection, quality of life for transplantation patients would be increased alongside a reduced need for RE-transplants.