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CD4⁺ Th Cells Resembling Regulatory T Cells That Inhibit Chronic Colitis Differentiate in the Absence of Interactions Between CD4 and Class II MHC ¹

Timothy L. Denning^*,, Hai Qi, Rolf König^*, Kevin G. Scott, Makoto Naganuma and Peter B. Ernst^2,

Departments of ^* Microbiology and Immunology, Pediatrics, and Pathology, University of Texas Medical Branch, Galveston, TX 77555; and Digestive Health Center of Excellence and Department of Internal Medicine, University of Virginia, Charlottesville, VA 22908

Regulatory CD4⁺ Th cells can prevent many autoimmune diseases; however, the factors selecting for these cells remain poorly defined. In transgenic mice with a mutation in the CD4 binding region on class II MHC, the disruption of CD4-class II interactions selected for CD4⁺ Th cells that expressed surface markers and cytokines associated with regulatory Th cells. Th cells from these mice were enriched for CD45RB^low as well as CD25⁺, while they expressed high levels of the transcription factor associated with regulatory T cells, Foxp3, and cytokines, including IL-4, IL-10, and IFN- mRNA and protein. These regulatory Th cells inhibited the function of APCs via IL-10 production, and adoptive transfer of these cells prevented weight loss and inflammation in a model of colitis. CD4⁺ regulatory Th cells emerged only when interactions between CD4 and class II MHC were deficient on cells of nonhemopoietic origin. These data support a novel model controlling the differentiation of regulatory Th cells and suggest that interactions between CD4 and class II MHC may a useful target for re-educating T cells as a treatment for inflammatory diseases.

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