# TCR-dependent activation, functional differentiation and memory formation of CD4+ T cells following infection

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $497,938

## Abstract

Project Summary
 Because of their elevated frequency, ability to self-renew and rapid acquisition of effector function
following re-activation, memory T cells have an enhanced ability to protect from secondary challenge. The
generation of memory T cells is the focal point of numerous vaccine and immunotherapeutic strategies. Most
(90-95%) effector T cells die after pathogen clearance, but those fated to become memory cells can be
identified during the primary effector response, showing that activated T cells receive differentiation cues
during the primary response to infection that influence memory fate differentiation. We have recently shown
that T cell receptor (TCR) signals play a key role in driving CD4+ memory T cell differentiation. TCRs that are
able to engage MHC Class II-bound antigen (pMHCII) in sustained interactions are biased towards the
formation of long-lived memory, while TCRs that engage in short-lived interactions with antigen are biased
towards terminal effector cell differentiation. We will build on those studies by using diverse infectious models
to define aspects of the TCR-dependent activation and transcriptional program that leads to the formation of
lymphoid-resident, circulating and tissue-resident CD4+ memory T cells. We pose three key questions. First,
what is the role of TCR signal strength in the formation of memory T cells? We will explore the hypothesis that
increasing TCR signal strength in vivo drives terminal effector T cell differentiation, while weaker TCR signal
strength allows memory T cell formation. Second, what are the TCR binding parameters associated with
memory T cell development? We will measure 2D affinity and bond lifetime with the application of force for
TCRs at that are effector-biased or memory-biased. We will test the hypothesis that bond lifetimes will predict
TCR-dependent memory differentiation. Third, what are the transcriptional programs that control memory
formation? We will test the mechanistic role of molecules that are differentially expressed in memory T cell
precursors during the primary effector response, including TCF-1. We anticipate that resolution of the
questions posed in this study will provide a framework for determining in greater mechanistic detail how
memory T cells form and identify therapeutic approaches for directly modulating CD4+ effector and memory T
cell differentiation in vivo.

## Key facts

- **NIH application ID:** 9831123
- **Project number:** 5R01AI137248-03
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Matthew A Williams
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $497,938
- **Award type:** 5
- **Project period:** 2018-01-17 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9831123

## Citation

> US National Institutes of Health, RePORTER application 9831123, TCR-dependent activation, functional differentiation and memory formation of CD4+ T cells following infection (5R01AI137248-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9831123. Licensed CC0.

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