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PMID: 12949259 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

CD4+CD25+ T regulatory cells control anti-islet CD8+ T cells through TGF-beta-TGF-beta receptor interactions in type 1 diabetes.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 100 ·No. 19 ·2003-09-16 ·Pages 10878-83

Green EA, Gorelik L, McGregor CM, Tran EH, Flavell RA

Abstract

Pancreatic lymph node-derived CD4+CD25+ T regulatory (Treg) cells inhibit in situ differentiation of islet-reactive CD8+ T cells into cytotoxic T lymphocytes, thereby preventing diabetes progression. The mechanism by which these Treg cells suppress anti-islet CD8+ T cells is unknown. Here, we show by using a CD8+ T cell-mediated model of type 1 diabetes that transforming growth factor (TGF)-beta-TGF-beta receptor signals are critical for CD4+CD25+ Treg cell regulation of autoreactive islet-specific cytotoxic T lymphocytes. Transgenic expression of tumor necrosis factor alpha from birth to 25 days of age in the islets of B6 mice that constitutively express CD80 on their beta cells results in accumulation of CD4+CD25+TGF-beta+ cells exclusively in the islets and pancreatic lymph nodes, which delays diabetes progression. In contrast, expression of tumor necrosis factor alpha until 28 days of age prevents islet accumulation of CD4+CD25+TGF-beta+ Treg cells, resulting in acceleration to diabetes. Furthermore, adoptive transfer experiments demonstrated that CD4+CD25+ Treg cells could not control naïve or activated islet-reactive CD8+ T cells bearing a dominant negative TGF-beta receptor type II. Our data demonstrate that, in vivo, TGF-beta signaling in CD8+ T cells is critical for CD4+CD25+ Treg cell suppression of islet-reactive CD8+ T cells in type 1 diabetes.

MeSH Terms
Adoptive Transfer Animals CD4 Antigens/immunology CD8-Positive T-Lymphocytes/immunology Diabetes Mellitus, Type 1/immunology,metabolism Islets of Langerhans/immunology Mice Mice, Inbred C57BL Pancreas/pathology Receptors, Interleukin-2/immunology Receptors, Transforming Growth Factor beta/metabolism Signal Transduction Transforming Growth Factor beta/metabolism
Chemicals
CD4 Antigens Receptors, Interleukin-2 Receptors, Transforming Growth Factor beta Transforming Growth Factor beta
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Green E Allison
Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, Cambridge University, United Kingdom. allison.green@cimr.cam.ac.uk
Gorelik Leonid
McGregor Catrin M
Tran Elise H
Flavell Richard A
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.1834400100
Email
allison.green@cimr.cam.ac.uk
Published
2003-09-16
Epub
2003-00-29
Pages
10878-83
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC196896
Subset
IM
Grants
NIDDK NIH HHS · R01 DK051665 · United States
NIDDK NIH HHS · R01 DK51665 · United States
External Links
PubMed source DOI: 10.1073/pnas.1834400100 PMC Full Text View journal details
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