# Role of the CD43 Receptor on Effector CD8+ T Cells During Acute Allograft Rejection

> **NIH NIH R56** · JOHNS HOPKINS UNIVERSITY · 2024 · $327,500

## Abstract

PROJECT SUMMARY
 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-4 Ig derivative) 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-4 Ig in
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 cel...

## Key facts

- **NIH application ID:** 11125031
- **Project number:** 1R56AI179856-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Scott M Krummey
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $327,500
- **Award type:** 1
- **Project period:** 2024-08-08 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11125031

## Citation

> US National Institutes of Health, RePORTER application 11125031, Role of the CD43 Receptor on Effector CD8+ T Cells During Acute Allograft Rejection (1R56AI179856-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/11125031. Licensed CC0.

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