The autoimmune regulator Aire is a key mediator of central tolerance for peripherally restricted antigens. Its absence in human patients results in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. The cellular signals that regulate Aire expression are undefined. We show here that lymphotoxin signaling is necessary for the expression of Aire and its downstream target genes. The failure of Aire induction in the thymi of lymphotoxin-deficient and lymphotoxin-beta receptor-deficient mice contributes to overt autoimmunity against self antigens normally protected by Aire. Conversely, stimulation of lymphotoxin-beta receptor by agonistic antibody leads to increased expression of Aire and tissue-restricted antigens in both intact thymi and cultured thymic epithelial cell line. These findings define the essential cross-talk between thymocytes and thymic stroma that is required for central tolerance.

Herpesvirus entry mediator (HVEM), a TNF receptor superfamily member, has been previously described as a T cell costimulatory receptor. Surprisingly, HVEM-/- T cells showed enhanced responses to in vitro concanavalin A (ConA) stimulation when compared with WT T cells. Consistent with these findings, HVEM-/- mice exhibited increased morbidity and mortality as compared with WT mice in a model of ConA-mediated T cell-dependent autoimmune hepatitis. HVEM-/- mice produced higher levels of multiple cytokines, which were dependent on the presence of CD4+ T cells. Furthermore, HVEM-/- mice were more susceptible to MOG peptide-induced experimental autoimmune encephalopathy, and they showed increased T cell proliferation and cytokine production in response to antigen-specific challenge. Taken together, our data revealed an unexpected regulatory role of HVEM in T cell-mediated immune responses and autoimmune diseases.

Herpesvirus entry mediator (HVEM), a TNF receptor superfamily member, has been previously described as a T cell costimulatory receptor. Surprisingly, HVEM -/-T cells showed enhanced responses to in vitro concanavalin A (ConA) stimulation when compared with WT T cells. Consistent with these findings, HVEM -/-mice exhibited increased morbidity and mortality as compared with WT mice in a model of ConA-mediated T cell-dependent autoimmune hepatitis. HVEM -/-mice produced higher levels of multiple cytokines, which were dependent on the presence of CD4 + T cells. Furthermore, HVEM -/-mice were more susceptible to MOG peptide-induced experimental autoimmune encephalopathy, and they showed increased T cell proliferation and cytokine production in response to antigen-specific challenge. Taken together, our data revealed an unexpected regulatory role of HVEM in T cell-mediated immune responses and autoimmune diseases.

γδ T cells are a multifaceted group of cells which have both innate and adaptive characteristics and functions. Although they are most commonly known for their response to mycobacterium and their locations at mucosal sites, their roles in autoimmunity are still unclear. γδ T cells have been seen in the CSF and lesions of Multiple Sclerosis patients and although their function is not entirely understood, it is clear these cells may have roles in regulating autoimmune inflammation in the CNS. Recent studies have focused on the role of γδ T cells in MS and EAE as both pathogenic and protective, their functions within the CNS, the types of subsets and a possible role in Th17 inflammation. In this review we will examine the data acquired from both human patients and the murine models of MS, experimental autoimmune encephalomyelitis (EAE), in order to gain a clear picture of how γδ T cells influence pathogenesis of EAE and MS.

γδ T cells are resident in cerebrospinal fluid and central nervous system (CNS) lesions of multiple sclerosis (MS) patients, but as multifaceted cells exhibiting innate and adaptive characteristics, their function remains unknown. Previous studies in experimental autoimmune encephalomyelitis (EAE) are contradictory and identified these cells as either promoting or suppressing disease pathogenesis. This study examines distinct γδ T cell subsets during EAE and indicates they mediate differential functions in CNS inflammation and demyelination resulting in pathogenesis or protection. We identified two γδ subsets in the CNS, Vγ1+ and Vγ4+, with distinct cytokine profiles and tissue specificity. Anti-γδ T cell receptor (TCR) monoclonal antibody (mAb) administration results in activation and downregulation of surface TCR, rendering the cells undetectable, but with opposing effects: anti-Vγ4 treatment exacerbates disease whereas anti-Vγ1 treatment is protective. The Vγ4+ subset produces multiple proinflammatory cytokines including high levels of IL-17, and accounts for 15-20% of the interleukin-17 (IL-17) producing cells in the CNS, but utilize a variant transcriptional program than CD4+ Th17 cells. In contrast, the Vγ1 subset produces CCR5 ligands, which may promote regulatory T cell differentiation. γδ T cell subsets thus play distinct and opposing roles during EAE, providing an explanation for previous reports and suggesting selective targeting to optimize regulation as a potential therapy for MS.

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Although elevated levels of IgE in asthmatic patients are strongly associated with lung infiltration by activated T helper (Th) 2 cells, the physiological role of immunoglobulin E (IgE) in the airway remains largely undefined. Lymphotoxin-deficient α (LTα−/−) mice exhibit increased airway inflammation, paradoxically accompanied by diminished levels of IgE and reduced airway hyperresponsiveness in response to both environmental and induced antigen challenge. The severe lung inflammation in LTα−/− mice is Th1 in nature and can be alleviated by IgE reconstitution. Conversely, depletion of IgE in wild-type mice recapitulates the lung pathologies of LTα−/− mice. Therefore, this work has revealed that lymphotoxin is essential for IgE production, and a physiological role of IgE in the airway may consist of maintaining the balance of Th1 and Th2 responses to prevent aberrant inflammation.

The engagement of CD137 (4-1BB), an inducible T cell costimulatory receptor and member of the TNF receptor superfamily, by agonistic Abs can promote strong tumor and viral immunity mediated by CD8+ T cells and stimulate IFN-γ production. However, its role in Th2-mediated immune responses has not been well defined. To address this issue, we studied the function of CD137 engagement using an allergic airway disease model in which the mice were sensitized with inactivated Schistosoma mansoni eggs followed by S. mansoni egg Ag challenge directly in the airways and Th1/2 cytokine production was monitored. Interestingly, treatment of C57BL/6 mice with agonistic anti-CD137 (2A) during sensitization completely prevents allergic airway inflammation, as shown by a clear inhibition of T cell and eosinophil infiltration into the lung tissue and airways, accompanied by diminished Th2 cytokine production and reduced serum IgE levels, as well as a reduction of airway hyperresponsiveness. At various time points after immunization, restimulated splenocytes from 2A-treated mice displayed reduced proliferation and Th2 cytokine production. In accordance with this, agonistic Ab to CD137 can directly coinhibit Th2 responses in vitro although it costimulates Th1 responses. CD137-mediated suppression of Th2 response is independent of IFN-γ and T regulatory cells. Our study has identified a novel pathway to inhibit Th2 responses in a CD137-dependent fashion.