# Mechanisms of ligand discrimination by the T cell signaling machinery

> **NIH NIH R35** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $390,000

## Abstract

SUMMARY
T cells can discriminate between diseased and non-diseased states. To make this distinction, the information
provided by extracellular receptors must be interpreted by signaling networks within the T cell. Most notable is T
cell antigen receptor (TCR) signaling network because it combines a receptor that scans the surface of human
cells for threats and signaling proteins that ensure a highly sensitive and specific response. This TCR signaling
machinery can detect small quantities of an antigenic agonist and discriminate it from a background of structurally
similar endogenous ligands. The overarching goal of my research group is to elucidate how the TCR signaling
machinery discriminates between TCR ligands by producing distinct signaling outcomes. The past few decades
have revealed how the TCR is coupled to signaling proteins within the T cell, but much less is known about how
these signaling proteins are coordinated to produce different cellular responses, such as whether a TCR ligand
should be ignored, or cause the T cell to become activated. The underlying mechanisms used to produce context-
specific TCR signals must be determined to fully realize the potential of T cells as therapeutic entities for the
treatment of human disease. Regulatory mechanisms can diversify signaling by controlling the activity of
signaling proteins, such as kinases, and their assembly into protein complexes. We propose to determine how
TCR signal diversification can arise from (1) negative feedback loops, (2) differential assembly of signaling
complexes, and (3) adaptive desensitization of TCR signaling. To interrogate these mechanisms of signal
diversification and their effect on a T cell response, we will combine chemical tools with immunological
approaches. We will use proximity labeling and mass spectrometry analyses to determine how the composition
of signaling complexes is altered by kinase-responsive negative feedback and TCR-ligand binding properties.
We will also evaluate more long-term mechanisms of receptor desensitization caused by adaptive transcriptional
changes by RNA sequencing. These datasets will be generated and analyzed with our collaborators at the
University of Michigan Medical School, which includes the Proteomics Resource Facility and Advanced
Genomics Core.

## Key facts

- **NIH application ID:** 10499251
- **Project number:** 1R35GM146813-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Adam Courtney
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $390,000
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10499251

## Citation

> US National Institutes of Health, RePORTER application 10499251, Mechanisms of ligand discrimination by the T cell signaling machinery (1R35GM146813-01). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10499251. Licensed CC0.

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