The population dynamics of T lymphocytes is an increasingly topical issue because of its important medical ramifications. An individual's pool of T cells is homeostatically regulated, integrating cell input, proliferation and death to maintain a remarkably constant total count. The focus of this proposal is maintenance of the naive T cell compartment, in particular the roles of T cell receptor (TCR) engagement of major histocompatibility complex (MHC) molecules and interleukin (IL)-7 receptor (R) binding of IL-7, both known to be required for na?ve T cells to persist for prolonged periods in the peripheral lymphoid organs. Performant systems permitting T cell-specific, tetracycline (tet)-regulatable expression of TCR and MHC class II molecules in mouso already exist, as does a protocol for monoclonal antibody blockade of IL-7R. These will be employed to 1) evaluate the interplay between TCR and IL-7R- mediated survival signals at the cellular level and 2) evaluate the interplay between TCR- and IL-7R-mediated survival signals at the molecular level. In addition, a novel system will be engineered in order to 3) generate, characterize and utilize mice expressing IL-7R on T cells in a tet-regulatable fashion. Specific hypotheses that will be addressed include the notion that the signaling pathways emanating from the TCR and IL-7R intersect and the speculation that IL-7R acts as a homeostatic sensor for the naive T cell compartment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI051530-04
Application #
6881094
Study Section
Immunobiology Study Section (IMB)
Program Officer
Nabavi, Nasrin N
Project Start
2002-04-01
Project End
2007-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
4
Fiscal Year
2005
Total Cost
$420,000
Indirect Cost
Name
Joslin Diabetes Center
Department
Type
DUNS #
071723084
City
Boston
State
MA
Country
United States
Zip Code
02215
Zemmour, David; Zilionis, Rapolas; Kiner, Evgeny et al. (2018) Single-cell gene expression reveals a landscape of regulatory T cell phenotypes shaped by the TCR. Nat Immunol 19:291-301
Zemmour, David; Pratama, Alvin; Loughhead, Scott M et al. (2017) Flicr, a long noncoding RNA, modulates Foxp3 expression and autoimmunity. Proc Natl Acad Sci U S A 114:E3472-E3480
Yissachar, Nissan; Zhou, Yan; Ung, Lloyd et al. (2017) An Intestinal Organ Culture System Uncovers a Role for the Nervous System in Microbe-Immune Crosstalk. Cell 168:1135-1148.e12
Glatman Zaretsky, Arielle; Konradt, Christoph; Dépis, Fabien et al. (2017) T Regulatory Cells Support Plasma Cell Populations in the Bone Marrow. Cell Rep 18:1906-1916
Panduro, Marisella; Benoist, Christophe; Mathis, Diane (2016) Tissue Tregs. Annu Rev Immunol 34:609-33
Dépis, Fabien; Kwon, Ho-Keun; Mathis, Diane et al. (2016) Unstable FoxP3+ T regulatory cells in NZW mice. Proc Natl Acad Sci U S A 113:1345-50
Tan, Tze Guan; Mathis, Diane; Benoist, Christophe (2016) Singular role for T-BET+CXCR3+ regulatory T cells in protection from autoimmune diabetes. Proc Natl Acad Sci U S A 113:14103-14108
Magnuson, Angela M; Thurber, Greg M; Kohler, Rainer H et al. (2015) Population dynamics of islet-infiltrating cells in autoimmune diabetes. Proc Natl Acad Sci U S A 112:1511-6
Sefik, Esen; Geva-Zatorsky, Naama; Oh, Sungwhan et al. (2015) MUCOSAL IMMUNOLOGY. Individual intestinal symbionts induce a distinct population of ROR?? regulatory T cells. Science 349:993-7
Mingueneau, Michael; Krishnaswamy, Smita; Spitzer, Matthew H et al. (2014) Single-cell mass cytometry of TCR signaling: amplification of small initial differences results in low ERK activation in NOD mice. Proc Natl Acad Sci U S A 111:16466-71

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