Molecular basis of multiple sclerosis development
Type I regulatory (Tr1) cells, a type of T cell, undoubtedly have a critical part to play in MS. Impaired Tr1 cell production is a hallmark of the disease, and when production is induced in a mouse MS model, inflammation of the CNS is prevented. Another important molecule is interleukin-27 (IL-27), a key inducer of Tr1 that mediates its immunosuppressive effects. The TR1 CELLS project has produced a detailed analysis of IL-27 mediated Tr1 induction to identify targets that could be manipulated to suppress autoimmunity of the CNS. Researchers using microarray analysis of Tr1 treated cells identified two transcription factors, IRF1 and BATF that are required for Tr1 differentiation. Using a mouse model of human MS, tests indicated that IRF1 and BATF play a role in the development of autoimmunity. IRF1 deficient mice do not recover after the peak of the disease is reached but further deteriorate. Cells isolated from the knockout mice produced decreased amounts of IL-10. Transferred into sick wild type mice and treated with IL-27, both IRF1 and BATF deficient mice failed to suppress MS. Moreover, IRF-knockout mice developed spontaneous mouse MS when six weeks old as opposed to the wildtype littermates that remained healthy. Results also show that IRF1 and BATF bind to regulatory regions in the IL-10 locus in a cooperative way – binding of IRF1 is dependent on the presence of BATF, and vice versa. Overall, the evidence points to IRF1 and BATF being pioneering factors for differentiation of Tr1 cells. IRF1 is a smaller-scale/focused pioneer factor, whereas BATF acts globally. Integration of data resulted in a transcriptional regulatory model for both IRF1- and BATF-deficient Tr1 cells. This suggests a dramatically altered transcriptional state for BATF-deficient Tr1 cells, mediated by several layers of altered transcriptional regulatory interactions. TR1 CELLS have created a clear picture of the molecular interplay between BATF and IRF1, a process necessary for the production of Tr1 cells. As malfunctioning Tr1 cells are present in MS patients, the results will serve as a knowledge base for targeted therapy.
Keywords
MS, Tr1 cell, TR1 CELLS, IRF1, BATF
