# Dissecting the interactions between TCR signaling strength and inhibitory pathways

> **NIH NIH K08** · UNIVERSITY OF CHICAGO · 2024 · $186,840

## Abstract

PROJECT SUMMARY/ABSTRACT
 This 5-year K08 training program is designed to facilitate my (Dr. Lin Shen) career development in
preparation of my independent research career as a physician-scientist. My long-term goal is to study the
pathogenesis and, potentially, the therapy of autoimmune diseases. This proposal focuses on how inhibitory
pathways restrain abnormal TCR signaling strength to achieve peripheral tolerance. Central guidance and the
training environment will be provided by my primary mentor, Dr. Arthur Weiss, an expert in TCR signaling.
Further expertise will be provided by a strong advisory panel of experts in lymphocyte signaling, immune
tolerance, autoimmunity and transcriptomic profiling. A training plan with experimental research, didactics, and
seminars has been developed to advance me towards my career goals. The extensive resources and support
at the UCSF will facilitate my pathway to independence and my long-term goals.
 Dysregulation of TCR signaling has long been recognized to play important roles in the pathogenesis of
autoimmune diseases. However, how inhibitory pathways are engaged by enhanced TCR signaling strength to
regulate peripheral tolerance and prevent autoimmunity remains incompletely understood. The cytoplasmic
tyrosine kinase ZAP70 plays a requisite role in TCR signaling. Two ZAP70 hypermorphic mutants, the stronger
W131A and the weaker R360P, interfere with autoinhibition and have varying effects on TCR signaling. As a
consequence of enhanced basal signaling, OTII-TCR transgenic W131A T cells exhibit marked upregulation of
inhibitory receptors and acquisition of an anergic phenotype. The ZAP70 R360P mouse mutant that I
generated derives from a familial severe autoimmune syndrome. R360P mice failed to develop overt
autoimmune disease on a C57BL/6 background but exhibited expansion of regulatory and anergic T cells.
Strikingly, OTI-TCR transgenic R360P T cells showed enhanced responses to weak and self-peptides.
Introducing deficiency in Cbl-b, a negative regulator for TCR signaling, resulted in enhanced R360P-OTI T cell
responses to a weak agonist peptide and reversed functional anergy in W131A-OTII T cells. Therefore, I
hypothesize that increased TCR signaling strength renders T cells subject to greater control by inhibitory
pathways but may confer upon them greater sensitivity to disruption of these inhibitory pathways. In this
proposal, I will take advantage of the R360P and W131A mouse models to study how enhanced TCR signaling
strength and inhibitory pathways are coupled together to either maintain or subvert peripheral tolerance. In Aim
1, using a range of biochemical techniques and transcriptomic profiling, I will dissect how TCR signaling
strength is dynamically coupled to inhibitory programs. In Aim 2, I will study whether augmented TCR signaling
strength promotes sensitivity to the disruption of negative regulatory pathways. This study will provide new
mechanistic insights into how these opposing signal...

## Key facts

- **NIH application ID:** 10840974
- **Project number:** 5K08AI171160-04
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Lin Shen
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $186,840
- **Award type:** 5
- **Project period:** 2022-06-19 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10840974

## Citation

> US National Institutes of Health, RePORTER application 10840974, Dissecting the interactions between TCR signaling strength and inhibitory pathways (5K08AI171160-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10840974. Licensed CC0.

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