# Determinants of T Cell Fate in Transplantation Tolerance

> **NIH NIH R01** · EMORY UNIVERSITY · 2020 · $387,900

## Abstract

Seminal studies in mouse models and emerging data in NHP and patient populations have consistently
implicated memory T cells as being a formidable barrier to long-term, rejection-free allograft survival,
particularly in the setting of costimulation blockade. As such, work in our laboratory over the past several years
has focused on identifying new pathways that control memory T cell responses during transplantation.
FcγRIIB, the only inhibitory Fc receptor, inhibits intracellular signaling via the ITIM motif located in its
cytoplasmic region. FcγRIIB is known to be expressed by many immune cell types, including B cells, DCs,
macrophages and granulocytes; however, the general consensus for the past few decades has been that T
cells do not express this molecule. Work done in the last cycle of the grant published by our lab indicated that
FcγRIIB-/- mice exhibit increased costimulation blockade-resistant rejection relative to WT controls. This
increased rejection was not the result of increased antibody secretion, as no differences in anti-donor
antibodies were detected in these animals. Instead, we discovered that FcγRIIB is expressed on a subset of
memory CD8+ T cells generated via both transplantation and virally-elicited heterologous immunity, and that
blockade of this novel coinhibitory pathway results in enhanced donor-reactive memory CD8+ T cell responses.
Our data thus suggest a previously unidentified functional role for FcγRIIB coinhibitory signaling in regulating
CD8+ memory T cells during transplantation. However, the mechanisms underlying this observation, including
the identity of the FcγRIIB ligand in this system (i.e. endogenous antibody vs. Fc-containing biologic), remain
unknown. Compellingly, our new preliminary data reveal that the degree of expression of FcγRIIB on donor-
reactive CD8+ memory T cell populations directly correlated with susceptibility of those cells to costimulation
blockade, providing further evidence for a T cell-intrinsic role for FcγRIIB coinhibitory signaling in
transplantation. Overall, these data suggest a novel mechanism by which the production of alloantibody may
function as a negative feedback loop to prevent alloreactive CD8+ T cell activation, and raise the possibility of
an innovative new approach to controlling donor-reactive CD8+ memory T cells during transplantation. Thus, in
this proposal we aim to further interrogate the mechanisms by which FcγRIIB inhibitory signaling regulates
donor-reactive memory CD8+ T cell responses in transplantation by determining the T cell intrinsic role of
FcγRIIB signaling, identifying the FcγRIIB ligand in this system (endogenous antibody/immune complexes vs.
Fc-containing biologics), and interrogating the epigenetic and transcription-factor mediated control of FcγRIIB
expression on donor-reactive CD8+ memory T cells during transplantation.

## Key facts

- **NIH application ID:** 9813501
- **Project number:** 5R01AI073707-09
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Mandy L Ford
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,900
- **Award type:** 5
- **Project period:** 2008-06-25 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9813501

## Citation

> US National Institutes of Health, RePORTER application 9813501, Determinants of T Cell Fate in Transplantation Tolerance (5R01AI073707-09). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9813501. Licensed CC0.

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