Deciphering the function of CREB in regulatory T cells - regulator for type one versus type two immune-responses?
Final Report Abstract
Regulatory T (Treg) cells are one of the most important players to prevent autoimmune disease and maintain immune homeostasis. The underlying mechanisms, which promote differentiation of Treg cells, are of utmost therapeutic importance and therefore a matter of intensive research. Previous studies describe that the transcriptional activator CREB induces generation and promotes maintenance of Treg cells by direct transcriptional mechanisms. In our project we demonstrate that in mice with a Foxp3-specific knockout of CREB, enhanced numbers of Tregs are found in vivo in spleen, lung and colon. These Tregs display a reduced Foxp3 expression, but enhanced expression of the IL-33 receptor (ST-2), IL-10, IL-13, and CREM. ST-2 positive Tregs are particularly prominent at non-lymphoid tissues and the CREB deficient Tregs were highly suppressive in vitro and prevented disease activity in CD4 T cell mediated transfer colitis in an IL-10 and CREM dependent way. Vice versa, enhanced disease activity was observed in an ovalbumin-induced asthma mouse model. Furthermore, these mice were highly susceptible in an TLR7 dependent lupus nephritis mouse model. Mechanistically, in cooperation with CREM, CREB expression in Tregs alters chromatin accessibility to the ST-2 region and thereby influences T cell specific immune responses mediated by IL-10.
