Immunity is mediated by memory cells, which are derived from naive lymphocytes that proliferate and differentiate in response to vaccination or primary infection. Based on evidence from CD8+ T cells, it is currently thought that immune memory comes about because antigenic stimulation causes short-lived naive cells to become stem cell-like, self-renewing memory cells that persist at a stable level for the life of the host. However, during the last funding period we found that: (1) the number of memory CD4+ T cells in the whole body declines after exposure to antigen;(2) the rate of decline for one clonal memory cell population was identical to the rate of decline for that clone in its naive state, and (3) polyclonal naive CD4+ T cells have complex survival characteristics consistent with a mixture of clones with individual half-lives ranging from weeks to years. Based on these findings, we propose to test a new model of immune memory for CD4+ T cells in which individual naive clones vary greatly in their inherent survival times based on their unique TCR and give rise to memory cells with the same survival characteristics as their naive precursor. This model will be tested by measuring the survival times of naive and memory CD4+ T cells from different TCR transgenic clones, determining whether or not polyclonal long-lived naive CD4+ T cells give rise to long-lived memory cells, assessing changes in TCR usage in the naive T cell repertoire over time, determining whether or not naive CD4+ T cells from a TCR transgenic line made one year after immunization are long-lived, assessing the signals required to maintain short and long-lived CD4+ T cell clones, and determining whether or not memory CD4+ T cells undergo self-renewing proliferation. Successful completion of this proposal has the potential to produce a paradigm shift in our understanding of the mechanism of CD4+ T cell memory and suggest new vaccine and immunotherapy strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI039614-14
Application #
7727929
Study Section
Cellular and Molecular Immunology - B (CMI)
Program Officer
Lapham, Cheryl K
Project Start
1996-04-01
Project End
2010-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
14
Fiscal Year
2010
Total Cost
$345,948
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
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
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
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
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
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
Tubo, Noah J; Pagán, Antonio J; Taylor, Justin J et al. (2013) Single naive CD4+ T cells from a diverse repertoire produce different effector cell types during infection. Cell 153:785-96

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