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, and their generation is the focal point of numerous vaccine strategies. However, recent studies have demonstrated that the differentiation of effector and memory CD4+ T cells following acute infection with intracellular pathogens differs in key respects from that of CD8+ T cells. In particular, the events that recruit CD8+ T cells into the immune response are also sufficient to enable all subsequent differentiation stages, including effector and memory differentiation. CD4+ T cells, on the other hand, undergo progressive stages of differentiation. They also require a longer stimulatory period to undergo robust primary and secondary expansion as compared to CD8+ T cells. We have recently found that some CD4+ T cell clones within the immune response can undergo robust expansion and a measure of effector differentiation but fail to populate the memory pool. This failure corresponds to lower TCR avidity and higher expression of the pro-apoptotic molecule Bim as compared to other CD4+ T cell responders. Furthermore, we also observed that while CD4+ memory T cell populations declined over time, the most long-lived clones maintained the highest functional avidity for antigen (as defined by the ability to produce IFN3 in response to decreasing concentrations of antigen). These results suggest a model in which increasing TCR signals promote a hierarchical differentiation of CD4+ T cells, progressively driving clonal expansion, effector differentiation, memory differentiation and finally the differentiation of memory populations capable of stable, long- term persistence. While previous studies have suggested a role for high avidity TCR interactions with antigen in selecting CD4+ effector T cell responders, we will attempt to define the role that these interactions play in the selection of CD4+ memory T cell populations as well as in the stimulation of robust secondary responses. To do this we will undertake a thorough characterization of the TCR repertoire of CD4+ effector and memory populations in the response to acute infection. We will further specify the role of the pro-apoptotic mediator Bim in the selection of high TCR avidity CD4+ memory T cell repertoires. Broadly, we will test the hypothesis that as antigenic signals increase during the primary response, CD4+ T cells undergo hierarchical stages of differentiation, with the strongest signals resulting in stable CD4+ memory T cell populations.

Public Health Relevance

The induction of memory T cells is a fundamental component of the immune system's ability to provide protection from previously encountered infectious pathogens. In this project we will explore the requirements for the establishment of CD4+ memory T cells capable of long-term survival and protection. Understanding these requirements is a pre-requisite to the design of more effective vaccination and immunotherapeutic strategies aimed at inducing CD4+ T cell-mediated protective immunity, with particular relevance to diseases for which more effective vaccines are desirable, such as AIDS, malaria, tuberculosis and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI080830-05
Application #
8604667
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Lapham, Cheryl K
Project Start
2010-02-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2014
Total Cost
$331,898
Indirect Cost
$109,148
Name
University of Utah
Department
Pathology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Kim, Chulwoo; Jay, David C; Williams, Matthew A (2014) Dynamic functional modulation of CD4+ T cell recall responses is dependent on the inflammatory environment of the secondary stimulus. PLoS Pathog 10:e1004137
Mitchell, Diana M; Williams, Matthew A (2013) Disparate roles for STAT5 in primary and secondary CTL responses. J Immunol 190:3390-8
Jay, David C; Mitchell, Diana M; Williams, Matthew A (2013) Bim mediates the elimination of functionally unfit Th1 responders from the memory pool. PLoS One 8:e67363
Kim, Chulwoo; Wilson, Theodore; Fischer, Kael F et al. (2013) Sustained interactions between T cell receptors and antigens promote the differentiation of CD4ýýý memory T cells. Immunity 39:508-20
Khanolkar, Aaruni; Williams, Matthew A; Harty, John T (2013) Antigen experience shapes phenotype and function of memory Th1 cells. PLoS One 8:e65234