# T cell receptor-activated autophagy as a regulator of T cell effector responses

> **NIH NIH R01** · HENRY M. JACKSON FDN FOR THE ADV MIL/MED · 2020 · $615,143

## Abstract

Project Summary/Abstract
 Engagement of the T cell receptor (TCR) initiates a complex cascade of stimulatory and regulatory
signals that orchestrate highly precise control of T cell proliferation, survival and differentiation. We have
recently defined TCR-induced autophagy (TCR-IA) as a novel mechanism that regulates TCR signal
transduction via highly selective degradation of key signaling molecules. We have shown that TCR-IA is
independent of Vps34, the class III phosphoinositol-3-kinase (PI3K) implicated in most autophagy pathways.
Our preliminary data suggest that TCR-IA is dependent on class I PI3K and inositol phosphatases, including
SHIP1/2 and Inpp4A/B. In studies of the terminal steps in TCR-IA, we have demonstrated that the selective
targeting of T cell signaling intermediates to autophagosomes requires a cytoplasmic signaling complex we
have named the “POLKADOTS signalosome,” in which the multi-functional adaptor molecule p62 plays a
central role. Our recent data show that the signaling adaptor, Bcl10, is targeted to the TCR-IA degradative
pathway via interaction with p62. We have also shown that degradation of the cyclin dependent kinase
inhibitor, p27, requires p62 expression, suggesting that p62 is a crucial component of a molecular machine (the
POLKADOTS signalosome) that directs TCR-IA-dependent proteolysis of specific targets.
 The purpose of our proposed studies is to elucidate the molecular mechanisms that connect antigenic
stimulation of the TCR to selective degradation of targets of TCR-IA, and to determine the consequences of
disruption of terminal steps in this pathway on T cell effector differentiation and function. We will achieve these
goals through three Aims. The goal of Aim 1 is to define the cytoplasmic signaling pathway by which TCR
signaling leads to de novo production of autophagosomes, with a particular emphasis on SHIP1/2 and
Inpp4A/B. Our studies in Aim 2 will determine the molecular mechanism by which p62 and POLKADOTS
signalosome partners direct TCR-induced selective autophagy of target molecules. In Aim 3, we will use an
inducible p62 knockout model to determine the role of p62 and p62-dependent TCR-IA in generation of in vivo
T cell effector responses. Together, we expect these data to define key molecular mechanisms in the TCR-IA
pathway, and to define how TCR-IA impacts T cell differentiation for control of pathogen infections. This work
may ultimately lead to novel and highly specific strategies for manipulation of in vivo T cell responses, which
may be applicable to diverse human diseases such as autoimmunity, transplant rejection, and cancer.

## Key facts

- **NIH application ID:** 9931135
- **Project number:** 5R01AI125552-04
- **Recipient organization:** HENRY M. JACKSON FDN FOR THE ADV MIL/MED
- **Principal Investigator:** THOMAS Patrick CONRADS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $615,143
- **Award type:** 5
- **Project period:** 2017-06-16 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9931135

## Citation

> US National Institutes of Health, RePORTER application 9931135, T cell receptor-activated autophagy as a regulator of T cell effector responses (5R01AI125552-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9931135. Licensed CC0.

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