Microbiome and Autoimmune Uveitis

Commensal microbes affect all aspects of immune development and homeostasis in health and disease. Increasing evidence points to the notion that the gut commensals impact not only intestinal diseases but also diseases in tissues distant from the gut. Autoimmune or non-infectious uveitis is a sight-threatening intraocular inflammation that affects the neuroretina. It is strongly T cell driven, but the precise causative mechanisms are not fully understood. We and others observed that depletion of gut microbiota in animal models of uveitis attenuated disease. Using a spontaneous model of the disease, we questioned how retina-specific uveitogenic T cells are primed when their cognate antigens are sequestered within the immune privileged eye. The data suggested that gut commensals provide a signal directly through the retina-specific T cell receptor and cause these autoreactive T cells to trigger uveitis. This activation of retina-specific T cells in the gut appears to be independent of the endogenous retinal antigen. Rather, the findings point to the notion that gut microbiota may mimic retinal antigen(s), however, the actual mimic has not yet been identified. Microbiota may also serve as an “adjuvant” providing innate signals that amplify and direct the host immune response for development of uveitis. In contrast, spontaneous uveitis that develops in AIRE−/− mice appears to be independent of gut microbiota. To date, available data on human microbiota in association with uveitis are very limited and causative relationships are difficult to establish. This review will summarize the current knowledge on the role of microbiome in uveitis and its underlying mechanisms, and discuss unresolved questions and issues in an attempt to explore the concept of gut-retina axis

Requirements for Selection of Conventional and Innate T Lymphocyte Lineages

SummaryMice deficient in the Tec kinase Itk develop a large population of CD8+ T cells with properties, including expression of memory markers, rapid production of cytokines, and dependence on Interleukin-15, resembling NKT and other innate T cell lineages. Like NKT cells, these CD8+ T cells can be selected on hematopoietic cells. We demonstrate that these CD8+ T cell phenotypes resulted from selection on hematopoietic cells—forcing selection on the thymic stroma reduced the number and innate phenotypes of mature Itk-deficient CD8+ T cells. We further show that, similar to NKT cells, selection of innate-type CD8+ T cells in Itk−/− mice required the adaptor SAP. Acquisition of their innate characteristics, however, required CD28. Our results suggest that SAP and Itk reciprocally regulate selection of innate and conventional CD8+ T cells on hematopoietic cells and thymic epithelium, respectively, whereas CD28 regulates development of innate phenotypes resulting from selection on hematopoietic cells

SAP regulates T cell–mediated help for humoral immunity by a mechanism distinct from cytokine regulation

X-linked lymphoproliferative disease is caused by mutations affecting SH2D1A/SAP, an adaptor that recruits Fyn to signal lymphocyte activation molecule (SLAM)-related receptors. After infection, SLAM-associated protein (SAP)−/− mice show increased T cell activation and impaired humoral responses. Although SAP−/− mice can respond to T-independent immunization, we find impaired primary and secondary T-dependent responses, with defective B cell proliferation, germinal center formation, and antibody production. Nonetheless, transfer of wild-type but not SAP-deficient CD4 cells rescued humoral responses in reconstituted recombination activating gene 2−/− and SAP−/− mice. To investigate these T cell defects, we examined CD4 cell function in vitro and in vivo. Although SAP-deficient CD4 cells have impaired T cell receptor–mediated T helper (Th)2 cytokine production in vitro, we demonstrate that the humoral defects can be uncoupled from cytokine expression defects in vivo. Instead, SAP-deficient T cells exhibit decreased and delayed inducible costimulator (ICOS) induction and heightened CD40L expression. Notably, in contrast to Th2 cytokine defects, humoral responses, ICOS expression, and CD40L down-regulation were rescued by retroviral reconstitution with SAP-R78A, a SAP mutant that impairs Fyn binding. We further demonstrate a role for SLAM/SAP signaling in the regulation of early surface CD40L expression. Thus, SAP affects expression of key molecules required for T–B cell collaboration by mechanisms that are distinct from its role in cytokine regulation

Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling

Endotoxin, a bacterial lipopolysaccharide (LPS), causes fatal septic shock via Toll-like receptor (TLR)4 on effector cells of innate immunity like macrophages, where it activates nuclear factor κB (NF-κB) and mitogen-activated protein (MAP) kinases to induce proinflammatory cytokines such as tumor necrosis factor (TNF)-α. Dok-1 and Dok-2 are adaptor proteins that negatively regulate Ras–Erk signaling downstream of protein tyrosine kinases (PTKs). Here, we demonstrate that LPS rapidly induced the tyrosine phosphorylation and adaptor function of these proteins. The stimulation with LPS of macrophages from mice lacking Dok-1 or Dok-2 induced elevated Erk activation, but not the other MAP kinases or NF-κB, resulting in hyperproduction of TNF-α and nitric oxide. Furthermore, the mutant mice showed hyperproduction of TNF-α and hypersensitivity to LPS. However, macrophages from these mutant mice reacted normally to other pathogenic molecules, CpG oligodeoxynucleotides, poly(I:C) ribonucleotides, or Pam3CSK4 lipopeptide, which activated cognate TLRs but induced no tyrosine phosphorylation of Dok-1 or Dok-2. Forced expression of either adaptor, but not a mutant having a Tyr/Phe substitution, in macrophages inhibited LPS-induced Erk activation and TNF-α production. Thus, Dok-1 and Dok-2 are essential negative regulators downstream of TLR4, implying a novel PTK-dependent pathway in innate immunity