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Major histocompatibility complex molecules regulate autoimmune diabetes through dendritic cells

The major histocompatibility complex (MHC) comprises a group of cell surface molecules that mediate interactions between immune cells. They determine, for example, the compatibility of donors and hosts for organ transplants. Genetically-encoded variation in MHC class II molecules has long been known to provide risk or afford resistance to multiple autoimmune diseases, including type 1 diabetes, albeit through very poorly understood mechanisms.

A work published in the American journal Proceedings of the National Academy of Sciences (PNAS) shows that anti-diabetogenic MHC class II molecules operate by promoting the differentiation of disease-promoting white blood cells into disease-suppressing ones. This research was led by Professor Pere Santamaria from the University of Calgary and ISIS scientist of IDIBAPS, in collaboration with Dr. Pau Serra, an IDIBAPS’ Ramón y Cajal investigator.

Working with nonobese diabetic (NOD) mice, the investigators unveiled the mechanisms through which MHC class II molecules promote resistance to type 1diabetes. They genetically engineered NOD mice to either express diabetes-promoting or -suppressing MHC class II molecules and compared the effects of these molecules on the development and function of diabetes-causing white blood cells.

These studies revealed that dendritic cells, a white blood cell type which is responsible for orchestrating most immune responses, can “trick” disease-causing (autoreactive) white blood cells into becoming disease-suppressing ones, by “presenting” the protective MHC molecules on their surface. The authors propose that this mechanism may underlie the association of MHC class II genetic variation with other autoimmune conditions.

Reference: Tsai S, Serra P, Clemente-Casares X, Yamanouchi J, Thiessen S, Slattery RM, Elliott JF, Santamaria P. Antidiabetogenic MHC class II promotes the differentiation of MHC-promiscuous autoreactive T cells into FOXP3+ regulatory T cells. Proc Natl Acad Sci U S A. 2013 Feb 26; 110(9): 3471-6. doi: 10.1073/pnas.1211391110. Epub 2013 Feb 11.