Mutations in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) cause Blau syndrome, an inflammatory disorder characterized by uveitis. The antimicrobial functions of Nod2 are well-established, yet the cellular mechanisms by which dysregulated Nod2 causes uveitis remain unknown. Here, we report a non-conventional, T cell-intrinsic function for Nod2 in suppression of Th17 immunity and experimental uveitis. Reconstitution of lymphopenic hosts with Nod2-/- CD4+ T cells or retina-specific autoreactive CD4+ T cells lacking Nod2 reveals a T cell-autonomous, Rip2-independent mechanism for Nod2 in uveitis. In naive animals, Nod2 operates downstream of TCR ligation to suppress activation of memory CD4+ T cells that associate with an autoreactive-like profile involving IL-17 and Ccr7. Interestingly, CD4+ T cells from two Blau syndrome patients show elevated IL-17 and increased CCR7. Our data define Nod2 as a T cell-intrinsic rheostat of Th17 immunity, and open new avenues for T cell-based therapies for Nod2-associated disorders such as Blau syndrome.

Lambda interferons (IFN-$\lambda$s) are a major component of the innate immune defense to viruses, bacteria, and fungi. In human liver, IFN-$\lambda$ not only drives antiviral responses, but also promotes inflammation and fibrosis in viral and non-viral diseases. Here we demonstrate that macrophages are primary responders to IFN-$\lambda$, uniquely positioned to bridge the gap between IFN-$\lambda$ producing cells and lymphocyte populations that are not intrinsically responsive to IFN-$\lambda$. While CD14+ monocytes do not express the IFN-$\lambda$ receptor, IFNLR1, sensitivity is quickly gained upon differentiation to macrophages in vitro. IFN-$\lambda$ stimulates macrophage cytotoxicity and phagocytosis as well as the secretion of pro-inflammatory cytokines and interferon stimulated genes that mediate immune cell chemotaxis and effector functions. In particular, IFN-$\lambda$ induced CCR5 and CXCR3 chemokines, stimulating T and NK cell migration, as well as subsequent NK cell cytotoxicity. Using immunofluorescence and cell sorting techniques, we confirmed that human liver macrophages expressing CD14 and CD68 are highly responsive to IFN-$\lambda$ ex vivo. Together, these data highlight a novel role for macrophages in shaping IFN-$\lambda$ dependent immune responses both directly through pro-inflammatory activity and indirectly by recruiting and activating IFN-$\lambda$ unresponsive lymphocytes.

CD4+ T cells, especially T-helper (Th) cells (Th1, Th2 and Th17) and regulatory T cells (Treg) play pivotal role in the pathogenesis of multiple sclerosis (MS), a demyelinating autoimmune disease occurring in central nervous system (CNS). Astragaloside IV (ASI, CAS: 84687-43-4) is one of the saponins isolated from Astragalus membranceus, a traditional Chinese medicine with immunomodulatory effect. So far, whether ASI has curative effect on experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and how it affects the subsets of CD4+ T cells, as well as the underlying mechanism have not been clearly elucidated. In the present study, ASI was found to ameliorate the progression and hamper the recurrence of EAE effectively in the treatment regimens. It significantly reduced the demyelination and inflammatory infiltration of CNS in EAE mice by suppressing the percentage of Th1 and Th17 cells, which was closely associated with the inhibition of JAK/STAT and NF-$\kappa$B signaling pathways. ASI also increased the percentage of Treg cells in spleen and CNS, which was accompanied by elevated Foxp3. However, in vitro experiments disclosed that ASI could regulate the differentiation of Th17 and Treg cells but not Th1 cells. In addition, it induced the apoptosis of MOG-stimulated CD4+ T cells probably through modulating STAT3/Bcl-2/Bax signaling pathways. Together, our findings suggested that ASI can modulate the differentiation of autoreactive CD4+ T cells and is a potential prodrug or drug for the treatment of MS and other similar autoimmune diseases.