Transplantation elicits a clonally diverse CD8+ T cell response that is comprised of potent CD43+ effectors.

CD8+ T cells mediate acute rejection of allografts, which threatens the long-term survival of transplanted organs. Using MHC class I tetramers, we find that allogeneic CD8+ T cells are present at an elevated naive precursor frequency relative to other epitopes, only modestly increase in number after grafting, and maintain high T cell receptor diversity throughout the immune response. While antigen-specific effector CD8+ T cells poorly express the canonical effector marker KLRG-1, expression of the activated glycoform of CD43 defines potent effectors after transplantation. Activated CD43+ effector T cells maintain high expression of the coreceptor induced T cell costimulator (ICOS) in the presence of CTLA-4 immunoglobulin (Ig), and dual CTLA-4 Ig/anti-ICOS treatment prolongs graft survival. These data demonstrate that graft-specific CD8+ T cells have a distinct response profile relative to anti-pathogen CD8+ T cells and that CD43 and ICOS are critical surface receptors that define potent effector CD8+ T cell populations that form after transplantation.

TIGIT agonism alleviates costimulation blockade-resistant rejection in a regulatory T cell-dependent manner.

Belatacept-based immunosuppression in kidney transplantation confers fewer off-target toxicities than calcineurin inhibitors but comes at a cost of increased incidence and severity of acute rejection, potentially due to its deleterious effect on both the number and function of Foxp3+ regulatory T cells (Tregs). TIGIT is a CD28 family coinhibitory receptor expressed on several subsets of immune cells including Tregs. We hypothesized that coinhibition through TIGIT signaling could function to ameliorate costimulation blockade-resistant rejection. The results demonstrate that treatment with an agonistic anti-TIGIT antibody, when combined with costimulation blockade by CTLA-4Ig, can prolong allograft survival in a murine skin graft model compared with CTLA-4Ig alone. Further, this prolongation of graft survival is accompanied by an increase in the frequency and number of graft-infiltrating Tregs and a concomitant reduction in the number of CD8+ T cells in the graft. Through the use of Treg-specific TIGIT conditional knockout animals, we demonstrated that the TIGIT-mediated reduction in the graft-infiltrating CD8+ T cell response is dependent on signaling of TIGIT on Foxp3+ Tregs. Our results highlight both the key functional role of TIGIT on Foxp3+ Tregs under conditions in which CTLA-4 is blocked and the therapeutic potential of TIGIT agonism to optimize costimulation blockade-based immunosuppression.

CD45RB Status of CD8+ T Cell Memory Defines T Cell Receptor Affinity and Persistence.

The identity of CD45 isoforms on the T cell surface changes following the activation of naive T cells and impacts intracellular signaling. In this study, we find that the anti-viral memory CD8+ T pool is unexpectedly comprised of both CD45RBhi and CD45RBlo populations. Relative to CD45RBlo memory T cells, CD45RBhi memory T cells have lower affinity and display greater clonal diversity, as well as a persistent CD27hi phenotype. The CD45RBhi memory population displays a homeostatic survival advantage in vivo relative to CD45RBlo memory, and long-lived high-affinity cells that persisted long term convert from CD45RBlo to CD45RBhi. Human CD45RO+ memory is comprised of both CD45RBhi and CD45RBlo populations with distinct phenotypes, and antigen-specific memory to two viruses is predominantly CD45RBhi. These data demonstrate that CD45RB status is distinct from the conventional central/effector T cell memory classification and has potential utility for monitoring and characterizing pathogen-specific CD8+ T cell responses.