Mature T cells persist within the body for indefinite periods of time, providing protection from a vast array of pathogens. A fraction of naive T cells survive for decades and some memory T cells survive for a lifetime without re-exposure to antigen. It is not known how the lifespan of T cells is regulated at the individual, cellular level or at the population level. Identification of the cellular and molecular interactions regulating the protracted persistence of both naive and memory T cells is essential to understanding T cell homeostasis and immunological memory. The goals of the experiments outlined in this proposal are to identify the molecular mediators of T cell survival downstream of the T cell receptor in naive T cells and determine if memory T cells utilize those same factors. Preliminary data suggest that a survival pathway may exist downstream of TCR:MHC interactions in which TCR signaling modulates expression of Early growth response (Egr) transcription factors and inhibitory DNA binding (Id) proteins (repressers of E protein transcription factors). We will test the hypothesis that interactions between TCR and self-peptide/MHC molecules and/or ligand independent TCR signaling support a gene-expression profile conducive to T cell survival. A new model system will be created to test if the activity of Egr transcription factors support the homeostasis/survival of naive, effector and memory T cells. To this end, a mouse model expressing a T cell specific, dominant-interfering form of Egr in a tetracycline-regulatable fashion will allow the """"""""turn-off of Egr-mediated transactivation at key stages of T cell maturation. The role of Id proteins in the homeostasis and survival of naive, effector and memory T cells will also be examined utilizing Id2-deficient mice. As the expression of Egr and Id molecules is maintained by TCR-derived signals in naive T cells, the role of TCR surface expression and Egr/ld activity in the homeostasis and/or survival of memory T cells will also be examined. Furthermore, the possibility that TCR, interleukin-7-receptor and/or interleukin-15-receptor-mediated signals may synergize in maintaining the memory population will be explored. These studies will improve our understanding of how the immune system recovers following treatment- or illness-induced lymphopenia (such as chemotherapy or HIV infection) and aid in the design of vaccines that provide long-lasting protection from infection. Moreover, by expanding our understanding of how lymphocyte populations are regulated, it will be possible to gain insight into how normal survival signals are co-opted and how homeostatic set points are overcome by cancer cells providing possible targets for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI067545-04
Application #
7623613
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Lapham, Cheryl K
Project Start
2006-06-01
Project End
2011-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
4
Fiscal Year
2009
Total Cost
$316,254
Indirect Cost
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Shaw, Laura A; BĂ©langer, Simon; Omilusik, Kyla D et al. (2016) Id2 reinforces TH1 differentiation and inhibits E2A to repress TFH differentiation. Nat Immunol 17:834-43
Chea, Sylvestre; Schmutz, Sandrine; Berthault, Claire et al. (2016) Single-Cell Gene Expression Analyses Reveal Heterogeneous Responsiveness of Fetal Innate Lymphoid Progenitors to Notch Signaling. Cell Rep 14:1500-1516
Almaden, Jonathan V; Liu, Yi C; Yang, Edward et al. (2016) B-cell survival and development controlled by the coordination of NF-?B family members RelB and cRel. Blood 127:1276-86
Stone, Erica L; Pepper, Marion; Katayama, Carol D et al. (2015) ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation. Immunity 42:239-251

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