Identification of a Highly Functional Effector CD8 ⁺ T Cell Program after Transplantation in Mice and Humans

Area of Science:

• Immunology
• Transplantation Biology
• Cellular Immunology

Background:

• Acute T cell mediated rejection is a primary cause of early allograft loss.
• Previous research identified graft-specific CD8+ T cells expressing CD43 (1B11 epitope) during acute rejection.

Purpose of the Study:

• To investigate the in vivo fate and clinical relevance of CD43+ CD8+ T cells in allograft rejection.
• To determine if targeting CD43 1B11 signaling can improve graft survival.

Main Methods:

• Adoptive transfer of CD43 1B11+ and CD43 1B11- CD8+ T cells.
• Treatment with CD43 1B11 monoclonal antibody (mAb).
• Analysis of human CD8+ T cells (CD43 1D4 clone) and scRNA-seq of graft-infiltrating cells from renal transplant patients.

Main Results:

• CD43+ ICOS+ phenotype identifies proliferative graft-specific CD8+ T cells during acute rejection.
• CD43 1B11 mAb treatment overcame costimulation-blockade induced tolerance in mice.
• CD43 1B11+ CD8+ T cells were more persistent post-transplant, with some CD43 1B11- cells converting to CD43 1B11+.
• Human CD43 1D4+ CD8+ T cells represent antigen-experienced cells and are efficient cytokine producers.
• scRNA-seq revealed SPN+ GCNT1+ CD8+ T cells with effector phenotypes in rejecting renal allografts.

Conclusions:

• CD43 1B11 expression marks a proliferative and persistent CD8+ T cell population in murine allograft rejection.
• An analogous population of antigen-experienced CD8+ T cells contributes to allograft rejection in humans.
• Targeting this CD8+ T cell subset may offer a novel therapeutic strategy for preventing graft loss.