During the last decade, regulatory T (Treg) cells have emerged as key regulators of immune responses to self-antigens, allergens, commensal microbiota, infectious agents and tumors. Our previous work and work by others showed that transcriptional factor FoxpS serves as a lineage specification factor of Treg cells (Fontenot et al., 2003;2005; Hori et al., 2003;Khattri et al., 2003). We also demonstrated that paucity of Treg cells due to loss-of-function mutations of the Foxp3 gene is responsible for highly aggressive, fatal systemic immune-mediated inflammatory lesions in mice and men (Fontenot et al., 2003;2005;Kim et al., 2007;Liston et al., 2007;Kim at al., 2009). Our recent studies of FoxpS expression and function provided critical novel insights into the biology of Treg cells and into cellular mechanisms of the immune homeostasis. Particularly relevant to the current grant application, was our finding that Treg cells utilize a subset of TCR distinct from that of effector T cells in the thymus and in the periphery (Hsieh et al., 2004; Hsieh et al., 2006). In agreement with studies of transgene-encoded TCR combined with transgene-encoded cognate ligand, we also found that TCR displayed by Treg cells exhibit a heightened reactivity towards self-peptide MHC class II complexes. The increased affinity TCR signals, together with additional signals, are essential for Treg cell differentiation and likely important for their function. The overall goal of this grant has been to explore a role for TCR signaling and specificity in Treg cell differentiation and function. Specifically, we have been addressing a role for MHC class II expressed on thymic epithelial cells and dendritic cells in generation of a functional repertoire of Treg cells (Aim 1 and 2), a role for dendritic and Treg cells, and TCR-MHC class II interactions in Treg cell maintenance in the periphery (Aim 2), and a role for TCR signaling in Treg cell differentiation and their ability to protect against immune- mediated inflammation (Aim 3).

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 #
4R37AI034206-21
Application #
8503680
Study Section
Special Emphasis Panel (NSS)
Program Officer
Quill, Helen R
Project Start
1992-09-01
Project End
2019-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
21
Fiscal Year
2014
Total Cost
$442,029
Indirect Cost
$193,279
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

Showing the most recent 10 out of 18 publications