Although the vitamin A metabolite retinoic acid (RA) plays a critical role in immune function, RA synthesis during infection is poorly understood. Here, we show that retinal dehydrogenases (Raldh), required for the synthesis of RA, are induced during a retinoid-dependent type-2 immune response elicited by Schistosoma mansoni infection, but not during a retinoid-independent anti-viral immune response. Vitamin A deficient mice have a selective defect in TH2 responses to S. mansoni, but retained normal LCMV specific TH1 responses. A combination of in situ imaging, intra-vital imaging, and sort purification revealed that alternatively activated macrophages (AAMφ) express high levels of Raldh2 during S. mansoni infection. IL-4 induces Raldh2 expression in bone marrow-derived macrophages in vitro and peritoneal macrophages in vivo. Finally, in vivo derived AAMφ have an enhanced capacity to induce Foxp3 expression in CD4+ cells through an RA dependent mechanism, especially in combination with TGF-β. The regulation of Raldh enzymes during infection is pathogen specific and reflects differential requirements for RA during effector responses. Specifically, AAMφ are an inducible source of RA synthesis during helminth infections and TH2 responses that may be important in regulating immune responses.
Vitamin A deficiency, a major global health concern, increases morbidity and death due to infectious diseases. For vitamin A to be utilized by the immune system, it must be metabolized into retinoic acid (RA), its active form. RA is a key determinant of T cell activity. However, its contribution to protective immunity during infection is poorly understood, as is the regulation of its synthesis in this context. We examined RA synthesis by immune cells responding to helminth infection and virus infection. While intestinal T cell responses were vitamin A-dependent during both infections, only T cell responses elicited by helminth infection were vitamin A-dependent in the liver. Consistent with this finding, the enzymes necessary for RA synthesis were expressed by inflammatory cells recruited to the liver during helminth, but not virus, infection. We identified alternatively-activated macrophages as a source of RA synthesis within immune cells responding to helminth infection and find that they can induce regulatory T cells. Our findings provide a better understanding of vitamin A utilization during infection and demonstrate that RA synthesis is an inducible component of protective immunity.