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

• Published in: Cell reports (Cambridge) 2023-08, Vol.42 (8), p.112993-112993, Article 112993
• Main Authors: Cohen, Gregory S., Kallarakal, Melissa A., Jayaraman, Sahana, Ibukun, Francis I., Tong, Katherine P., Orzolek, Linda D., Larman, H. Benjamin, Krummey, Scott M.
• Format: Article
• Language: English
• Subjects: alloimmunity; Antibodies; CD8-Positive T-Lymphocytes; costimulation blockade; CP: Immunology; CTLA-4 Antigen; effector CD8+ T cells; Epitopes; Interleukin-2; Transplantation, Homologous
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112993

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. [Display omitted] •CD8+ T cells specific for the Ld QL9+ epitope respond to allogeneic skin grafts•Graft-specific CD8+ T cells express activated CD43 during acute rejection•CD43+ CD8+ T cells are potent effectors that rapidly infiltrate graft tissue•CD28 blockade resistance may be mediated through ICOS costimulation on CD43+ TEFF CD8+ T cells mediate acute rejection, which is a barrier to long-term graft survival. Cohen et al. track endogenous graft-specific CD8+ T cells during acute rejection of skin grafts and find that potent effector CD8+ T cells are defined by the expression of the activated CD43 receptor.