The adaptive immune system protects the host from a second infection by generating infection-specific lymphocytes called memory cells. Memory cells come from a much larger population of effector cells, which are generated from rare nave cells that proliferate after antigen binds to their antigen receptors. The objective of this projec is to understand CD4+ memory T cell formation. This is a significant issue because CD4+ T cells control certain intracellular infections by using T cell antigen receptors (TCR) to recognize microbial peptides bound to MHCII molecules on infected host cells. We made an important step in the right direction during the last funding period by developing a peptide:MHCII tetramer-based cell enrichment method to track CD4+ memory T cell formation in vivo. We found that infection with Listeria monocytogenes (Lm) caused a population of ~100 Lm peptide:MHCII-specific nave CD4+ T cells to proliferate and form three types of effector cells: Th1 cells and two types of follicular helper cells, Tfh and GC-Tfh cells. Using a novel limiting dilution adoptiv transfer method, we found that different single nave cells produced effector cell populations with different Th1/Tfh/GC-Tfh patterns and that clonal effector cell populations yielded smaller memory cell populations with a similar pattern. Importantly, the effector and memory cell subset pattern produced by a nave clone was in part an intrinsic feature of its T cell receptor (TCR). I is now critical to understand the mechanisms that cause individual nave cells to bifurcate down the Th1 or Tfh effector cell pathways since this decision sets the memory cell pattern. Using robust single cell methods, we will address the hypothesis that TCR signal strength, dendritic cell subsets and innate cytokines influence how nave CD4+ T cells proliferate, undergo apoptosis, and form Th1, Tfh, or GC-Tfh effector cells. Since all clonal effector cell populations produce memory cell populations of a smaller size, it is critical to understand why most of the effector cells die and some survive as memory cells. We will perform experiments to determine whether all effector cells have a chance of becoming memory cells or whether a small subset of effector cells is fated to become memory cells as a result of an asymmetric cell division or by switching on a catabolic pathway. This research is innovative because it will employ novel technology to track the fates of single CD4+ T cells at key checkpoints.

Public Health Relevance

This project focuses on a significant lymphocyte population and the process by which cells within it make the life or death decisions that lead to immune memory. This work could produce new principles in cell biology that could be used to improve the efficacy of vaccines for recalcitrant infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI039614-23
Application #
9674311
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Kelly, Halonna R
Project Start
1996-04-01
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
23
Fiscal Year
2019
Total Cost
Indirect Cost
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
Goldberg, Michael F; Roeske, Elizabeth K; Ward, Lauren N et al. (2018) Salmonella Persist in Activated Macrophages in T Cell-Sparse Granulomas but Are Contained by Surrounding CXCR3 Ligand-Positioned Th1 Cells. Immunity 49:1090-1102.e7
Burrack, Adam L; Malhotra, Deepali; Dileepan, Thamotharampillai et al. (2018) Cutting Edge: Allograft Rejection Is Associated with Weak T Cell Responses to Many Different Graft Leukocyte-Derived Peptides. J Immunol 200:477-482
Pape, Kathryn A; Maul, Robert W; Dileepan, Thamotharampillai et al. (2018) Naive B Cells with High-Avidity Germline-Encoded Antigen Receptors Produce Persistent IgM+ and Transient IgG+ Memory B Cells. Immunity 48:1135-1143.e4
Kotov, Dmitri I; Kotov, Jessica A; Goldberg, Michael F et al. (2018) Many Th Cell Subsets Have Fas Ligand-Dependent Cytotoxic Potential. J Immunol 200:2004-2012
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
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
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
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
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
Linehan, Jonathan L; Dileepan, Thamotharampillai; Kashem, Sakeen W et al. (2015) Generation of Th17 cells in response to intranasal infection requires TGF-?1 from dendritic cells and IL-6 from CD301b+ dendritic cells. Proc Natl Acad Sci U S A 112:12782-7

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