# Mechanistic study of TCR signaling strength in CD8 T cell differentiation during pathogenesis of T1DM

> **NIH NIH F30** · MEDICAL COLLEGE OF WISCONSIN · 2022 · $51,752

## Abstract

Project Summary
Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by CD8 T cell-mediated destruction
of pancreatic beta cells. This leads to an inability to produce insulin and thus a lifelong dependence on exogenous
insulin, as is the case for over 1 million Americans. A recent phase II clinical trial has shown it is possible to delay
the time to onset of T1DM using a non-specific immunotherapy that promotes signaling through the T cell
receptor (TCR) to induce a state of T cell exhaustion. Recent studies have shown that CD8 T cells in chronic
infection and cancer are heterogeneous, consisting of self-renewing progenitor cells that give rise to both
cytolytic effector and non-cytolytic exhausted cells. However, CD8 T cell heterogeneity in T1DM and the
processes connecting TCR signaling and CD8 T cell differentiation are not yet fully understood. A better
understanding of these concepts is vital for developing more specific immunotherapies for T1DM. Therefore,
the overarching goal of this fellowship is to investigate the mechanisms by which TCR signaling affects
CD8 T cell differentiation in T1DM. Aim 1 will map the phenotypic, clonal, and energetic landscapes of
diabetogenic CD8 T cells. Aim 2 will investigate whether diabetogenic CD8 T cells can be selectively
exhausted via exogenous TCR stimulation. This project addresses knowledge gaps at the intersection of
immunology and T1DM research in order to obtain a better understanding of the role of CD8 T cells in the
pathogenesis of T1DM. This work will further scientific and clinical studies that aim to delay the onset of T1DM
in a more selective manner with fewer immunosuppressive adverse effects. This project will be conducted at the
Medical College of Wisconsin and the Versiti Wisconsin Blood Research Institute with the mentorship of 6
immunologists and biochemists to provide multidisciplinary fellowship training. These mentors and institutions
will provide excellent training in the form of rigorous hands-on experiments, insightful data analysis, focused
manuscript writing when publishing results, and attendance at local and national meetings in the fields of
immunology and T1DM. The results of this fellowship could lead to an improved understanding of how
fundamental mechanisms of CD8 T cell signaling and differentiation impact the immunopathology and
disease course of T1DM, in line with the mission of NIDDK.

## Key facts

- **NIH application ID:** 10468970
- **Project number:** 5F30DK127526-03
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Moujtaba Y Kasmani
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $51,752
- **Award type:** 5
- **Project period:** 2020-09-03 → 2024-09-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468970

## Citation

> US National Institutes of Health, RePORTER application 10468970, Mechanistic study of TCR signaling strength in CD8 T cell differentiation during pathogenesis of T1DM (5F30DK127526-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10468970. Licensed CC0.

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