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Section on Immunology and Immunogenetics, Joslin Diabetes Center, and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215

CORRESPONDENCE Christophe Benoist and Diane Mathis: cbdm{at}joslin.harvard.edu

Foxp3 is required for the generation and activity of CD4⁺CD25⁺ regulatory T (T reg) cells, which are important controllers of autoimmunity, including type-1 diabetes. To determine where T reg cells affect the diabetogenic cascade, we crossed the Foxp3 scurfy mutation, which eliminates T reg cells, with the BDC2.5 T cell receptor (TCR) transgenic mouse line. In this model, the absence of T reg cells did not augment the initial activation or phenotypic characteristics of effector T cells in the draining lymph nodes, nor accelerate the onset of T cell infiltration of the pancreatic islets. However, this insulitis was immediately destructive, causing a dramatic progression to overt diabetes. Microarray analysis revealed that T reg cells in the insulitic lesion adopted a gene expression program different from that in lymph nodes, whereas T reg cells in draining or irrelevant lymph nodes appeared very similar. Thus, T reg cells primarily impinge on autoimmune diabetes by reining in destructive T cells inside the islets, more than during the initial activation in the draining lymph nodes.

Z. Chen and A.E. Herman contributed equally to this work.

A.E. Herman's present address is Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121.

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