Abstract
Following their activation in response to inflammatory signals, innate immune cells secrete T cell polarizing cytokines that promote the differentiation of naïve CD4 T cells into T helper (Th) cell subsets. Amongst these, Th17 cells play a prominent role in the development of a number of autoimmune diseases. Although regarded primarily as an immunosuppressant signal, cAMP has been found to mediate pro-inflammatory effects of macrophage-derived prostaglandin E2 (PGE2) on Th17 cells. Here we show that PGE2 enhances Th17 cell differentiation via the activation of the CREB co-activator CRTC2. Following its dephosphorylation, CRTC2 stimulates the expression of the cytokines IL-17A and IL-17F by binding to CREB over both promoters. CRTC2 mutant mice have decreased Th17 cell numbers, and they are protected from experimental autoimmune encephalitis, a model for multiple sclerosis. Our results suggest that small molecule inhibitors of CRTC2 may provide therapeutic benefit to individuals with autoimmune disease.
Highlights
Following their activation in response to inflammatory signals, innate immune cells secrete T-cell-polarizing cytokines that promote the differentiation of naive CD4 T cells into T helper (Th) cell subsets
T helper 17 (Th17) cells secrete factors such as IL-17A and IL-17F to recruit neutrophils and macrophages for pathogen clearance[5]. Both IL-17A and IL-17F appear critical for Th17 function, as mice deficient in these two cytokines are resistant to a mouse model of multiple sclerosis called experimental autoimmune encephalomyelitis (EAE)[6,7]
Naive CD4 T cells from both groups differentiated comparably into Th1, Th2 and regulatory T (Treg) cells in vitro (Fig. 1a,b), the differentiation of Crtc[2] À / À cells into Th17 cells was significantly impaired (Fig. 1b); IL-17A and IL17F cytokine expression was reduced in CRTC2 mutant relative to control (Fig. 1c)
Summary
Following their activation in response to inflammatory signals, innate immune cells secrete T-cell-polarizing cytokines that promote the differentiation of naive CD4 T cells into T helper (Th) cell subsets. T helper 17 (Th17) cells promote clearance of pathogens such as Mycobacterium tuberculosis and Candida albicans[1]; they are implicated in autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and asthma Following their activation, innate immune cells secrete cytokines such as transforming growth factor (TGF)-b and interleukin (IL)-6, which promote the differentiation of naive CD4 T cells into Th17 cells[2,3,4]. CAMP is thought to function primarily as an immunosuppressant signal; it inhibits nearly every pathway downstream of the T-cell receptor to suppress T-cell activation, proliferation and cytokine production[12] Despite these effects, T cells deficient in cAMP signalling due to targeted disruption of the Ga unit of the heterotrimeric G protein show a block in Th17 cell differentiation and inflammatory responsiveness[13]. Mice expressing a dominant-negative CREB polypeptide exhibit defects in proliferation, IL-2 production and impaired T-cell function[16,17]
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