Recent studies suggested that regulatory T cells (Tr) expressing transcription factor Foxp3 play a key role in keeping in check autoreactive T cells escaping negative selection in the thymus and peripheral tolerance induction. During previous funding period, we found protective Tr cells themselves utilize TCR with a heightened reactivity towards self-peptide MHC class II complexes. The increased affinity TCR signals together with additional poorly understood signals are likely essential for the differentiation of Tr cells. Nevertheless, TCR specificity requirement for Tr mediated protection against autoimmunity and the contribution of distinct APC types to Tr generation in the thymus and their maintenance and function in the periphery remain unknown. Several types of thymic APC can contribute to differentiation of Tr cells and we hypothesize that the ability of the Tr population to protect against autoimmune inflammation in distinct tissues and organs is differentially shaped by particular types of thymic and peripheral MHC class II expressing APC. In the current proposal we will employ a unique set of genetic tools to test these hypotheses by investigating the suppressive potential of Tr cells selected by the thymic cortical epithelial cells alone or together with the thymic medullary epithelial cells or dendritic cells to prevent autoimmune lesions in various organs. We will also examine how the repertoire of TCR displayed by Tr cells is shaped by MHC class II molecules displayed by distinct types of APC. Finally, we will test a requirement for distinct types of APC for thymic differentiation and peripheral maintenance of Tr cells, expressing a single TCR, and examine the ability of these cells to prevent autoimmunity. Together, the studies described in the current application will provide novel insights into cellular mechanisms involved in differentiation and maintenance of a functional protective repertoire of regulatory T cells.

Public Health Relevance

Regulatory T cells recently emerged as a key mechanism preventing autoimmunity and excessive tissue damage in the course of the immune response to viral, bacterial, and parasitic infections. Furthermore, these cells greatly diminish anti-tumor immunity. In studies described in this application, we will investigate the ways a functional protective repertoire of regulatory T cells is shaped during their differentiation. This work will lead to a better understanding of powerful protection against immune-inflicted damage of specific organs and tissues afforded by regulatory T cells and facilitate development of novel therapeutic approaches to treatment of autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI034206-17
Application #
7766910
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Rothermel, Annette L
Project Start
1992-09-01
Project End
2014-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
17
Fiscal Year
2010
Total Cost
$469,260
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Azizi, Elham; Carr, Ambrose J; Plitas, George et al. (2018) Single-Cell Map of Diverse Immune Phenotypes in the Breast Tumor Microenvironment. Cell 174:1293-1308.e36
Campbell, Clarissa; Dikiy, Stanislav; Bhattarai, Shakti K et al. (2018) Extrathymically Generated Regulatory T Cells Establish a Niche for Intestinal Border-Dwelling Bacteria and Affect Physiologic Metabolite Balance. Immunity 48:1245-1257.e9
Hsin, Jing-Ping; Lu, Yuheng; Loeb, Gabriel B et al. (2018) The effect of cellular context on miR-155-mediated gene regulation in four major immune cell types. Nat Immunol 19:1137-1145
Fan, Xiying; Moltedo, Bruno; Mendoza, Alejandra et al. (2018) CD49b defines functionally mature Treg cells that survey skin and vascular tissues. J Exp Med 215:2796-2814
Levine, Andrew G; Mendoza, Alejandra; Hemmers, Saskia et al. (2017) Corrigendum: Stability and function of regulatory T cells expressing the transcription factor T-bet. Nature 550:142
Green, Jesse A; Arpaia, Nicholas; Schizas, Michail et al. (2017) A nonimmune function of T cells in promoting lung tumor progression. J Exp Med 214:3565-3575
Bolotin, Dmitriy A; Poslavsky, Stanislav; Davydov, Alexey N et al. (2017) Antigen receptor repertoire profiling from RNA-seq data. Nat Biotechnol 35:908-911
Levine, Andrew G; Mendoza, Alejandra; Hemmers, Saskia et al. (2017) Stability and function of regulatory T cells expressing the transcription factor T-bet. Nature 546:421-425
Levine, Andrew G; Hemmers, Saskia; Baptista, Antonio P et al. (2017) Suppression of lethal autoimmunity by regulatory T cells with a single TCR specificity. J Exp Med 214:609-622
Li, Ming O; Rudensky, Alexander Y (2016) T cell receptor signalling in the control of regulatory T cell differentiation and function. Nat Rev Immunol 16:220-33

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