In this Top Read, Nagai et al. (p. 2293) report the mechanism by which UDP inhibits pathologic type 2 immunity–mediated inflammation. Bone marrow–derived macrophages (BMMs) were isolated from control mice and mice lacking the gene for the UDP-specific type 6 purinergic (P2Y6) receptor, P2ry6, which were sensitized to the house dust mite Dermatophagoides farinae (Df). When pretreated with UDP, BMMs lacking P2Y6 maintained only basal levels of secreted IL-12p40, whereas control mice showed increased secretion of IL-12p40, suggesting that P2Y6 enhances Df-induced cytokine production. Blocking calcium signaling in control BMMs reduced UDP-enhanced cytokine release, suggesting the involvement of calcineurin-dependent activation of the NFAT family of transcription factors. Of the three NFAT isoforms expressed in BMMs, only NFATC2 translocated to the nucleus in response to UDP priming, and Nfatc2−/− BMMs showed no such UDP-dependent potentiation. The authors then treated P2ry6-deficient mice with Df and adoptively transferred either Nfatc2−/− or wild-type (WT) BMMs into the mouse lungs, which showed that reintroduction of NFATC2 in BMMs alone restores IL-12p40 and IFN-γ production in bronchoalveolar lavage. Compared to WT, Nfatc2−/− mice sensitized to Df displayed an enhanced type 2 inflammation response, including lower expression of IFN-γ, IL-12β, and increased eosinophils. Altogether, the data suggest that endogenous UDP acts on macrophages via NFATC2 downstream of P2Y6 during the initial exposure to allergen. This pathway then enhances macrophage cytokine release to restrain the innate response and avoid pathological immune responses to innocuous immunogens.

A single nucleotide polymorphism (G307S) in the gene encoding DNAM-1, expressed in CD4+ T cells, is associated with many autoimmune diseases. In this Top Read, Murata et al. (p. 2304) showed that G307S DNAM-1 is a gain-of-function mutation that enhances proinflammatory CD4+ T cell responses. Conventional CD4+ T cells expressing G307S DNAM-1 had increased levels of proinflammatory cytokine production, compared with their wild-type (WT) counterparts. However, IL-10 production was unaffected by G307S DNAM-1 expression. Lck recruitment was enhanced in the G307S DNAM-1 mutants, compared with WT, subsequently increasing tyrosine phosphorylation and mediating the costimulatory effect of DNAM-1 on conventional CD4+ T cell activity. G307S DNAM-1 CD4+ T cells adoptively transferred into mice lead to elevated disease scores for experimental autoimmune encephalomyelitis, increased inflammatory cell infiltration and demyelination, and a greater number of CD4+ T cells producing proinflammatory cytokines in the spinal cord. Together, these data show that the G307S mutation of DNAM-1 enhances its costimulatory capability to amplify conventional CD4+ T cell inflammatory responses.