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 #
5R01DK051665-12
Application #
7477315
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
2008-08-01
Budget End
2009-07-31
Support Year
12
Fiscal Year
2008
Total Cost
$305,440
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
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
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
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