Role of the CD43 receptor on effector CD8+ t… (R56AI179856) – Project Grant to The Johns Hopkins University

Abstract: Despite excellent short-term outcomes after transplantation, the long-term survival of transplanted organs has stagnated for several decades. Recent clinical studies have demonstrated that acute cellular rejection, which is mediated by alloreactive t cells, is a risk factor for later graft failure. In order to effectively prevent acute rejection, deeper understanding of how t cells response to allogeneic antigen are needed. The CD28 pathway blocker belatacept (a ctla-4DERIVATIVE) offers significant long-term benefits versus calcineurin inhibitors for kidney transplant patients, but has limited efficacy in restraining CD8+ t cells and acute cellular rejection. Despite a great body of work investigating the programming of effector CD8+ t cells (teff) that respond to infections, relatively little is known about CD8+ teff that respond to allogeneic antigen in the context of an allograft. We found that after grafting, a subset of CD8+ teff expressing the activated CD43 isoform (defined by the 1B11 epitope) are formed during acute effector timepoints from day 7-21 post-graft. CD43 is a cellular receptor that influences t cell receptor signaling cascades and cellular trafficking, but its role in transplantation is undefined. Relative to other teff subsets, CD43+ teff appeared highly activated, displayed vigorous effector functions, and drove accelerated graft rejection. In human renal transplant patients, CD43+ CD8+ t cells infiltrate the kidney allografts of patients treated with belatacept, and CD43+ CD8+ t cells are functionally resistant to ctla-4IN vitro. Together, these data form the premise for our hypothesis that CD43+ teff are a potent effector population that can be targeted to limit acute rejection following transplantation. In this proposal, we will use an innovative MHC class i tetramer to characterize the role of CD43 on graft-specific CD8+ t cells. Specific aims: first, we will define the effector mechanisms that distinguish CD43+ teff function as a population from CD43- teff. Using adoptive transfer approaches, we will investigate the differentiation pathways that lead from naïve CD8+ t cells to CD43+ teff, the mechanisms by which CD43+ teff traffic from the draining lymph nodes into graft tissue, and the role of the inducible t cell costimulator (icos) receptor signaling in the fate of CD43+ teff. Second, we will investigate the role of CD43 receptor signaling on CD8+ t cells. Using a CD43 knockout mouse model, we will interrogate the requirement of CD43 signaling for graft rejection, how CD43 controls t cell at the clonal level, and the role of CD43 in determining the quality of secondary memory responses. Third, we will explore the potential of CD43 as a therapeutic target to limit alloimmunity in humans and mice. We will evaluate whether targeted deletion of CD43+ teff in vivo with an antibody-drug conjugate can elicit tolerance in combination with CD28 blockade. We will explore whether human CD43+ CD8+ t cells are a significant contributor to alloreactivity and resistance to CD28 blockade. This proposal will generate deeper understanding of allogeneic teff that will lead to new strategies to restrain CD8+ t cells that mediate acute rejection.

Action	Obligated	Date
Amendment	-$1,117	Mar 5, 2026
Original award	$327,500	Aug 8, 2024

Role of the CD43 receptor on effector CD8+ t cells during acute allograft rejection

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