STING is an endoplasmic reticulum (ER) signaling adaptor that is essential for the type I Interferon response to DNA pathogens. Aberrant activation of STING is linked to the pathology of autoimmune and autoinflammatory diseases. The rate-limiting step for the activation of STING is its translocation from the ER to the ER–Golgi intermediate compartment. Here we found that deficiency in the Ca 2+ sensor STIM1 caused spontaneous activation of STING and enhanced expression of type I interferons under resting conditions in mice and a patient suffering from combined immunodeficiency. Mechanistically, STIM1 associated with STING to retain it in the ER membrane, and co-expression of full-length or a STING-interacting fragment of STIM1 suppressed the function of dominant STING mutants that cause autoinflammatory diseases. Furthermore, deficiency in STIM1 strongly enhanced the expression of type I interferons after viral infection and prevented the lethality of infection with a DNA virus in vivo. This work delineates a STIM1–STING circuit that maintains the resting state of the STING pathway.

Contributions of humoral and cellular immunity in controlling neurotropic mouse hepatitis virus persistence within the CNS were determined in B cell-deficient JHD and syngeneic H-2d B cell+ Ab-deficient mice. Virus clearance followed similar kinetics in all mice, confirming initial control of virus replication by cellular immunity. Nevertheless, virus reemerged within the CNS of all Ab-deficient mice. In contrast to diminished T cell responses in H-2b B cell-deficient μMT mice, the absence of B cells or Ab in the H-2d mice did not compromise expansion, recruitment into the CNS, or function of virus-specific CD4+ and CD8+ T cells. The lack of B cells and lymphoid architecture thus appears to manifest itself on T cell responses in a genetically biased manner. Increasing viral load did not enhance frequencies or effector function of virus-specific T cells within the CNS, indicating down-regulation of T cell responses. Although an Ab-independent antiviral function of B cells was not evident during acute infection, the presence of B cells altered CNS cellular tropism during viral recrudescence. Reemerging virus localized almost exclusively to oligodendroglia in B cell+ Ab-deficient mice, whereas it also replicated in astrocytes in B cell-deficient mice. Altered tropism coincided with distinct regulation of CNS virus-specific CD4+ T cells. These data conclusively demonstrate that the Ab component of humoral immunity is critical in preventing virus reactivation within CNS glial cells. B cells themselves may also play a subtle role in modulating pathogenesis by influencing tropism.

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CD8+ T cells infiltrating the CNS control infection by the neurotropic JHM strain of mouse hepatitis virus. Differential susceptibility of infected cell types to clearance by perforin or IFN-γ uncovered distinct, nonredundant roles for these antiviral mechanisms. To separately evaluate each effector function specifically in the context of CD8+ T cells, pathogenesis was analyzed in mice deficient in both perforin and IFN-γ (PKO/GKO) or selectively reconstituted for each function by transfer of CD8+ T cells. Untreated PKO/GKO mice were unable to control the infection and died of lethal encephalomyelitis within 16 days, despite substantially higher CD8+ T cell accumulation in the CNS compared with controls. Uncontrolled infection was associated with limited MHC class I up-regulation and an absence of class II expression on microglia, coinciding with decreased CD4+ T cells in CNS infiltrates. CD8+ T cells from perforin-deficient and wild-type donors reduced virus replication in PKO/GKO recipients. By contrast, IFN-γ-deficient donor CD8+ T cells did not affect virus replication. The inability of perforin-mediated mechanisms to control virus in the absence of IFN-γ coincided with reduced class I expression. These data not only confirm direct antiviral activity of IFN-γ within the CNS but also demonstrate IFN-γ-dependent MHC surface expression to guarantee local T cell effector function in tissues inherently low in MHC expression. The data further imply that IFN-γ plays a crucial role in pathogenesis by regulating the balance between virus replication in oligodendrocytes, CD8+ T cell effector function, and demyelination.

Herpes simplex virus type 1 (HSV-1) infections are widespread in developed countries, with estimates of seropositivity exceeding 50% (54). Primary infections in immunocompetent individuals are usually mild or even asymptomatic and result in lifelong latent infections in sensory ganglia and the central nervous system (CNS) (5). Reactivated HSV-1 can result in recurrent diseases of mucous membranes (e.g., gingivostomatitis and herpes labialis) and herpes keratitis, an immunopathological disease that is a leading cause of blindness (39). Also, HSV-1 is the most common cause of fatal, sporadic encephalitis in immunocompetent individuals (40, 56). Improvements in diagnosis and antiviral drug treatment have dramatically reduced the morbidity and mortality of HSV-1 encephalitis (HSE) (55), although some patients fail to respond or subsequently suffer neurological relapses after completing a standard treatment course (18,55).Clinical and animal model studies have clearly demonstrated the importance of genetic makeup in resistance to a broad range of infectious agents (15,41). In regard to HSV-1, C57BL/6 (B6) and related B10 mouse strains are resistant, while other strains, such A/J, BALB/c, 129S6 (129), and DBA/ 2J, are susceptible to fatal infections (21,23,25). In these animal models, mortality results from CNS infection. In prior studies, we defined the herpes resistance locus (Hrl) on mouse chromosome 6 as a major determinant of resistance (22, 25); however, ongoing studies indicate that resistance to HSE is genetically very complex, involving multiple interacting loci, with tumor necrosis factor playing a critical role (26) (unpublished results). The mechanism by which HSV-1 CNS infection causes death has not been defined. Counterintuitively, necropsy virus titers of nervous system tissues do not correlate with mouse resistance or susceptibility genotype (25,26). These and other observations have led to the suggestion that variation of the host inflammatory response may play a major role in determining HSV fatality. Intense inflammatory responses in CNS tissues in a mouse model of HSE have been reported, with tumor necrosis factor and macrophage chemoattractant protein 1 being expressed prominently (43). Also, in vitro and in vivo studies have shown that human and mouse microglia nonproductively infected with HSV-1 express a variety of proinflammatory cytokines and chemokines, consistent with their involvement in

Key Points miR-142 is an essential regulator of lymphocyte ontogenesis and is required for the generation of humoral and cellular immunity in mice. miR-142-3p regulates B-cell homeostasis by controlling expression of BAFF-R.

Neurotropic coronavirus infection of mice results in acute encephalomyelitis followed by viral persistence. Whereas cellular immunity controls acute infection, humoral immunity regulates central nervous system (CNS) persistence. Maintenance of serum Ab was correlated with tissue distribution of virus-specific Ab-secreting cells (ASC). Although virus-specific ASC declined in cervical lymph node and spleen after infectious virus clearance, virus-specific serum Ab was sustained at steady levels, with a delay in neutralizing Ab. Virus-specific ASC within the CNS peaked rapidly 1 wk after control of infectious virus and were retained throughout chronic infection, consistent with intrathecal Ab synthesis. Surprisingly, frequencies of ASC in the BM remained low and only increased gradually. Nevertheless, virus-specific ASC induced by peripheral infection localized to both spleen and BM. The data suggest that CNS infection provides strong stimuli to recruit ASC into the inflamed tissue through sustained up-regulation of the CXCR3 ligands CXCL9 and CXCL10. Irrespective of Ag deprivation, CNS retention of ASC coincided with elevated BAFF expression and ongoing differentiation of class II + to class II -CD138 + CD19 + plasmablasts. These results confirm the CNS as a major ASCsupporting environment, even after resolution of viral infection and in the absence of chronic ongoing inflammation. IntroductionThe preeminent goal of the immune system is to eliminate pathogens and establish immunological memory [1]. Both T cells and Ab participate in eliminating a variety of pathogens; however, sustained serum Ab is an important criteria for many vaccination strategies, as they provide the first line of defense against re-infection [2]. Upon Ag encounter in regional lymph nodes, B cells undergo clonal expansion in extrafollicular foci and within germinal centers [3,4].Rapidly activated B cells secrete low-affinity Ab but can undergo isotype switching and limited BCR hypermutation as they differentiate into plasmablasts [3]. In the milieu of accessory cells and cytokines, germinal center B cells undergo affinity maturation and ultimately differentiate into both Ab-secreting cells (ASC) and memory B cells. As Ag is depleted, ASC and memory B cells are detected with increasing frequency in BM [2], where both stromal cells and other resident cells provide soluble as well as contact-dependent survival signals, including CXCL12 and BAFF [5]. Ab secretion by terminally differentiated plasma cells is independent of both Ag and T cell regulation [2,6]. Long-lived ASC in BM and spleen maintain serum Ab, thus providing protective immunity to re-infection, sometimes for the [4,6]. In contrast to Ag encountered in the periphery, the regulation of B cell activation by Ag sequestered within the central nervous system (CNS) is less clear. The absence of dedicated lymphatic drainage and the presence of the blood brain barrier (BBB) limits Ag transport from the CNS into secondary lymphoid tissue as well as trafficking of both cells and macromolecule...

The gut commensal Bacteroides fragilis or its capsular polysaccharide A (PSA) can prevent various peripheral and CNS sterile inflammatory disorders. Fatal herpes simplex encephalitis (HSE) results from immune pathology caused by uncontrolled invasion of the brainstem by inflammatory monocytes and neutrophils. Here we assess the immunomodulatory potential of PSA in HSE by infecting PSA or PBS treated 129S6 mice with HSV1, followed by delayed Acyclovir (ACV) treatment as often occurs in the clinical setting. Only PSA-treated mice survived, with dramatically reduced brainstem inflammation and altered cytokine and chemokine profiles. Importantly, PSA binding by B cells is essential for induction of regulatory CD4 + and CD8 + T cells secreting IL-10 to control innate inflammatory responses, consistent with the lack of PSA mediated protection in Rag −/− , B cell- and IL-10-deficient mice. Our data reveal the translational potential of PSA as an immunomodulatory symbiosis factor to orchestrate robust protective anti-inflammatory responses during viral infections.