The Journal of Experimental Medicine
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Published 7 June 2004. doi:10.1084/jem.20040179
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 11, 1479-1489
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CD4+CD25+ T Regulatory Cells Dependent on ICOS Promote Regulation of Effector Cells in the Prediabetic Lesion

Ann E. Herman1, Gordon J. Freeman3, Diane Mathis1,2, and Christophe Benoist1,2

1 Section on Immunology and Immunogenetics, Joslin Diabetes Center, 2 Department of Medicine, Brigham and Women's Hospital, and 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215

Address correspondence to Diane Mathis, Section on Immunology and Immunogenetics, Joslin Diabetes Center and Dept. of Medicine, Brigham and Women's Hospital, Harvard Medical School, One Joslin Pl., Research 4th Fl., Boston, MA 02215. Phone: (617) 264-2743; Fax: (617) 264-2744; email: dm{at}joslin.harvard.edu; or Christophe Benoist. Phone: (617) 264-2742; Fax: (617) 264-2744; email: cb{at}joslin.harvard.edu

CD4+CD25+ T regulatory cells (Tregs) prevent autoimmune disease, yet little is known about precisely where they exert their influence naturally in a spontaneous autoimmune disorder. Here, we report that Tregs and T effector cells (Teffs) coexist within the pancreatic lesion before type 1 diabetes onset. We find that BDC2.5 T cell receptor transgenic animals contain a small subset of FoxP3 positive CD4+CD25+CD69– cells in the pancreas, actively turning over, expressing the clonotypic receptor, and containing functional regulatory activity. Gene expression profiling confirms that the CD4+CD25+CD69– cells in pancreatic tissue express transcripts diagnostic of regulatory cells, but with significantly higher levels of interleukin 10 and inducible costimulator (ICOS) than their lymph node counterparts. Blockade of ICOS rapidly converts early insulitis to diabetes, which disrupts the balance of Teffs and Tregs and promotes a very broad shift in the expression of the T regulatory–specific profile. Thus, CD4+CD25+69– Tregs operate directly in the autoimmune lesion and are dependent on ICOS to keep it in a nondestructive state.

Key Words: autoimmunity • diabetes • costimulation • tolerance • microarray

The online version of this article contains supplemental material.

Abbreviations used in this paper: FPR, false positive rate; ICOS, inducible costimulator; ILN, inguinal LN; MLN, mesenteric LN; PLN, pancreatic LN; Teff, T effector cell; Treg, T regulatory cell.


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