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 #
5R37AI034206-19
Application #
8211049
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
2012-02-01
Budget End
2013-01-31
Support Year
19
Fiscal Year
2012
Total Cost
$464,567
Indirect Cost
$219,542
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Moltedo, Bruno; Hemmers, Saskia; Rudensky, Alexander Y (2014) Regulatory T cell ablation causes acute T cell lymphopenia. PLoS One 9:e86762
Penaloza-MacMaster, Pablo; Kamphorst, Alice O; Wieland, Andreas et al. (2014) Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection. J Exp Med 211:1905-18
Gasteiger, Georg; Rudensky, Alexander Y (2014) Interactions between innate and adaptive lymphocytes. Nat Rev Immunol 14:631-9
Arvey, Aaron; van der Veeken, Joris; Samstein, Robert M et al. (2014) Inflammation-induced repression of chromatin bound by the transcription factor Foxp3 in regulatory T cells. Nat Immunol 15:580-7
Feng, Yongqiang; Arvey, Aaron; Chinen, Takatoshi et al. (2014) Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus. Cell 158:749-63
Levine, Andrew G; Arvey, Aaron; Jin, Wei et al. (2014) Continuous requirement for the TCR in regulatory T cell function. Nat Immunol 15:1070-8
Sakaguchi, Shimon; Vignali, Dario A A; Rudensky, Alexander Y et al. (2013) The plasticity and stability of regulatory T cells. Nat Rev Immunol 13:461-7
Bos, Paula D; Plitas, George; Rudra, Dipayan et al. (2013) Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy. J Exp Med 210:2435-66
Gasteiger, Georg; Hemmers, Saskia; Firth, Matthew A et al. (2013) IL-2-dependent tuning of NK cell sensitivity for target cells is controlled by regulatory T cells. J Exp Med 210:1167-78
Gasteiger, Georg; Hemmers, Saskia; Bos, Paula D et al. (2013) IL-2-dependent adaptive control of NK cell homeostasis. J Exp Med 210:1179-87

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