# Determinants of T Cell Fate in Transplantation Tolerance

> **NIH NIH R01** · EMORY UNIVERSITY · 2023 · $714,964

## Abstract

Transplantation is a cure for end stage organ failure, yet achieving “one transplant for life” remains elusive for
many transplant recipients due to immunologic rejection. Studies in mouse and NHP models and patient
populations have consistently implicated memory CD8+ T cells as playing a causal role in mediating
immunosuppression-resistant allograft rejection. Thus, the identification of the molecular mechanisms that
regulate memory CD8+ T cells responses remains an important goal for immunotherapy in clinical
transplantation. Fc receptors, previously known only to be expressed on B cells and innate immune cells, can
fine-tune immune cell activation based on the balance of activating and inhibitory Fc receptor signaling, much
like T cell costimulatory and coinhibitory molecules. During the last funding cycle we identified that the
inhibitory receptor FcγRIIB is also expressed on a subset of multi-functional effector/ memory CD8+ T cells in
mice and in humans, and showed that FcγRIIB functionally regulates CD8+ T cell immunity in a cell-
autonomous manner in both mice and in a human clinical trial. However, the mechanisms by which this occurs
are still not clear. First, the signals via which FcγRIIB ligation leads to T cell death are not known. We
discovered that FcγRIIB signaling on CD8+ T cells is not controlled by antibody ligation, but instead by a novel
immunosuppressive cytokine fibrinogen-like 2 (Fgl2). Moreover, our additional preliminary data suggest a
FcγRIIB SHIP1-dependent mechanism that leads to the induction of apoptosis. Thus, in Aim 1, we will
determine the cellular source of Fgl2 that is critical for FcγRIIB-mediated CD8+ T cell apoptosis, and
will use a proteomics approach to elucidate the proximal intracellular signaling molecules that associate with
FcγRIIB to promote caspase 3/7 activity. Second, we made the novel observation that FcγRIIB+ CD8+ T cells
exhibit increased expression of the ganglioside metabolic enzyme Gm2a, and that increased expression of
Gm2a mRNA in CD8+ T cells is associated with stability on minimal immunosuppression in a cohort of human
renal transplant recipients. These preliminary data form the premise for the hypothesis to be tested in Aim 2:
that Gm2a is a novel regulatory pathway that regulates transplant acceptance, potentially in an FcγRIIB-
dependent fashion. Finally, in Aim 3 we propose to directly measure FcγRIIB, Fgl2, and Gm2a expression in
CD8+ T cells isolated from a validation cohort of human renal transplant recipients, and to determine the
association between CD8+ T cell FcγRIIB and Gm2a expression and reduced alloimmunity and/or acute
rejection. These data will allow us to determine the ability of FcγRIIB/Gm2a-expressing T cells to be used as a
predictive biomarker to stratify the risk of rejection following transplantation. In sum, through these mechanistic
and translational studies, we will elucidate the fundamental molecular and cellular pathways of FcγRIIB-
mediated inhibition of CD...

## Key facts

- **NIH application ID:** 10672382
- **Project number:** 5R01AI164716-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Mandy L Ford
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $714,964
- **Award type:** 5
- **Project period:** 2022-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10672382

## Citation

> US National Institutes of Health, RePORTER application 10672382, Determinants of T Cell Fate in Transplantation Tolerance (5R01AI164716-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10672382. Licensed CC0.

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