Abstract

The development of autoimmunity is caused, in part by a failure of negative regulatory mechanisms which ordinarily prevent these diseases from occurring in non-susceptible individuals. Regulation is imposed by anti-inflammatory cytokines which mediate their action, at least in part through regulatory T cells. TGF-beta is, arguably the most important regulatory cytokine which acts at least in part through regulatory CD4+CD25+FoxP3+ positive T cells, and in part through control of other cell types. In this proposal, we will investigate how signaling of TGF-beta into autoaggressive and other T cells prevents the development of T1D, and how this regulation fails in the autoimmune susceptible NOD mouse. Second, we will determine the cellular origin of the TGF-beta which inhibits T1D development. It has been recently shown that anti-CD3 treatment is therapeutic in reversing T1D in humans that have recently developed Type 1 Diabetes. We will determine whether TGF-beta is instrumental in this process and we will elucidate the mechanism whereby this occurs.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK051665-15
Application #
8115071
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Spain, Lisa M
Project Start
1996-08-01
Project End
2012-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
15
Fiscal Year
2011
Total Cost
$299,361
Indirect Cost

  Institution

Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520

  Publications

Yu, Hua; Gagliani, Nicola; Ishigame, Harumichi et al. (2017) Intestinal type 1 regulatory T cells migrate to periphery to suppress diabetogenic T cells and prevent diabetes development. Proc Natl Acad Sci U S A 114:10443-10448
Ishigame, Harumichi; Zenewicz, Lauren A; Sanjabi, Shomyseh et al. (2013) Excessive Th1 responses due to the absence of TGF-? signaling cause autoimmune diabetes and dysregulated Treg cell homeostasis. Proc Natl Acad Sci U S A 110:6961-6
Wen, Li; Green, Elizabeth A; Stratmann, Thomas et al. (2011) In vivo diabetogenic action of CD4+ T lymphocytes requires Fas expression and is independent of IL-1 and IL-18. Eur J Immunol 41:1344-51
Flavell, Richard A; Sanjabi, Shomyseh; Wrzesinski, Stephen H et al. (2010) The polarization of immune cells in the tumour environment by TGFbeta. Nat Rev Immunol 10:554-67
Sanjabi, Shomyseh; Flavell, Richard A (2010) Overcoming the hurdles in using mouse genetic models that block TGF-beta signaling. J Immunol Methods 353:111-4
Sanjabi, Shomyseh; Zenewicz, Lauren A; Kamanaka, Masahito et al. (2009) Anti-inflammatory and pro-inflammatory roles of TGF-beta, IL-10, and IL-22 in immunity and autoimmunity. Curr Opin Pharmacol 9:447-53
Matza, Didi; Badou, Abdallah; Jha, Mithilesh K et al. (2009) Requirement for AHNAK1-mediated calcium signaling during T lymphocyte cytolysis. Proc Natl Acad Sci U S A 106:9785-90
Sanjabi, Shomyseh; Mosaheb, Munir M; Flavell, Richard A (2009) Opposing effects of TGF-beta and IL-15 cytokines control the number of short-lived effector CD8+ T cells. Immunity 31:131-44
Ouyang, Weiming; Beckett, Omar; Flavell, Richard A et al. (2009) An essential role of the Forkhead-box transcription factor Foxo1 in control of T cell homeostasis and tolerance. Immunity 30:358-71
Li, Ming O; Flavell, Richard A (2008) Contextual regulation of inflammation: a duet by transforming growth factor-beta and interleukin-10. Immunity 28:468-76

Showing the most recent 10 out of 26 publications