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.

Public Health Relevance

The development of immunological memory is a fundamental component of the immune system's ability to provide protection from previously encountered infectious pathogens. This project will determine how T cells, the central component of immunological memory, acquire the characteristics of memory that allow them to provide robust immune protection. Understanding these requirements is a pre-requisite to the design of more effective vaccination and immunotherapeutic strategies aimed at inducing protective immunity, with particular relevance to infectious diseases and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI137248-02
Application #
9626353
Study Section
Immunity and Host Defense (IHD)
Program Officer
Kelly, Halonna R
Project Start
2018-01-17
Project End
2022-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Utah
Department
Pathology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112