The long-term objective of this project is the elucidation of basic principles about CD4+ memory T cells that can be applied to the design of more effective vaccines. CD4+ memory T cells are part of the host's immune system that responds more quickly and strongly to the second exposure to a foreign antigen than it did to the first. During the last funding period we developed a sensitive new technique to track polyclonal peptide major histocompatibility complex class II molecule (pMHCII)-specific CD4+ T cells in normal mice and used it to study immune memory induced by bacterial infection. We found that acute infection with an attenuated strain of Listeria monocytogenes (LM) generated T-bet+ IFN-3-producing Th1 cells, a novel population of Tbet- cells of unknown function that depended on an unknown signal from B cells, and follicular helper cells (Tfh) that depended on pMHCII presentation by B cells. The Th1 cells and T-bet- cells became memory cells but the Tfh cells did not. In contrast, persistent infection with Salmonella typhimurium (ST) induced only T-bet+ cells, which were more stable and contained more "multifunctional" cells capable of making IFN- 3 and TNF than memory cells induced by acute LM infection. The goal of the current project is to understand how the CD4+ memory T cell subsets induced by these infections are generated and provide protective immunity. LM infection will be studied to determine how the T-bet- memory cells are generated, whether they are what have historically been called central memory cells, and how they help B cells and CD8+ T cells during the secondary immune response. This research is significant because it could give clues about how to improve vaccines against acute infections. ST infection will be studied with the goal of identifying which variety of CD4+ T cell is needed to control infections that threaten the lives of AIDS patients, determine how these cells are generated and provide protection, and ascertain whether they can ever become truly long-lived memory cells. This research is significant because it could fill the knowledge gap that currently prevents creation of more effective T cell-mediated vaccines. This research is innovative because it will employ novel technology to track the endogenous polyclonal CD4+ T cell response during infection, and because it is based on the new ideas that anatomically confined chronic pMHCII presentation without the involvement of B cells is the best way to generate multifunctional CD4+ T cells capable of controlling intracellular bacterial infections.

Public Health Relevance

This project focuses on a significant lymphocyte population and an important infection for which a vaccine capable of conferring long-term protection in humans does not exist. The innovative approach described in this application could lead to new principles that could be used to improve the efficacy of vaccines for Salmonella, and perhaps other persistent bacterial infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI039614-16
Application #
8258730
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Lapham, Cheryl K
Project Start
1996-04-01
Project End
2016-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
16
Fiscal Year
2012
Total Cost
$377,500
Indirect Cost
$127,500
Name
University of Minnesota Twin Cities
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Tubo, Noah J; Fife, Brian T; Pagan, Antonio J et al. (2016) Most microbe-specific naïve CD4⁺ T cells produce memory cells during infection. Science 351:511-4
Nelson, Ryan W; Rajpal, Miriam N; Jenkins, Marc K (2015) The Neonatal CD4+ T Cell Response to a Single Epitope Varies in Genetically Identical Mice. J Immunol 195:2115-21
Yang, Jessica A; Tubo, Noah J; Gearhart, Micah D et al. (2015) Cutting edge: Bcl6-interacting corepressor contributes to germinal center T follicular helper cell formation and B cell helper function. J Immunol 194:5604-8
Taylor, Justin J; Pape, Kathryn A; Steach, Holly R et al. (2015) Humoral immunity. Apoptosis and antigen affinity limit effector cell differentiation of a single naïve B cell. Science 347:784-7
Wiesner, Darin L; Specht, Charles A; Lee, Chrono K et al. (2015) Chitin recognition via chitotriosidase promotes pathologic type-2 helper T cell responses to cryptococcal infection. PLoS Pathog 11:e1004701
Linehan, Jonathan L; Dileepan, Thamotharampillai; Kashem, Sakeen W et al. (2015) Generation of Th17 cells in response to intranasal infection requires TGF-β1 from dendritic cells and IL-6 from CD301b+ dendritic cells. Proc Natl Acad Sci U S A 112:12782-7
Nelson, Ryan W; Beisang, Daniel; Tubo, Noah J et al. (2015) T cell receptor cross-reactivity between similar foreign and self peptides influences naive cell population size and autoimmunity. Immunity 42:95-107
Tubo, Noah J; Jenkins, Marc K (2014) TCR signal quantity and quality in CD4(+) T cell differentiation. Trends Immunol 35:591-596
Yang, Yi; Torchinsky, Miriam B; Gobert, Michael et al. (2014) Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature 510:152-6
Nelson, Ryan W; McLachlan, James B; Kurtz, Jonathan R et al. (2013) CD4+ T cell persistence and function after infection are maintained by low-level peptide:MHC class II presentation. J Immunol 190:2828-34

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