Regulatory T cells (T(reg)) expressing the transcription factor Foxp3 control the autoreactive components of the immune system. The development of T(reg) cells is reciprocally related to that of pro-inflammatory T cells producing interleukin-17 (T(H)17). Although T(reg) cell dysfunction and/or T(H)17 cell dysregulation are thought to contribute to the development of autoimmune disorders, little is known about the physiological pathways that control the generation of these cell lineages. Here we report the identification of the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) as a regulator of T(reg) and T(H)17 cell differentiation in mice. AHR activation by its ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin induced functional T(reg) cells that suppressed experimental autoimmune encephalomyelitis. On the other hand, AHR activation by 6-formylindolo[3,2-b]carbazole interfered with T(reg) cell development, boosted T(H)17 cell differentiation and increased the severity of experimental autoimmune encephalomyelitis in mice. Thus, AHR regulates both T(reg) and T(H)17 cell differentiation in a ligand-specific fashion, constituting a unique target for therapeutic immunomodulation.

Our understanding of the pathways that regulate lymphocyte metabolism, as well as the effects of metabolism and its products on the immune response, is still limited. We report that a metabolic program controlled by the transcription factors hypoxia inducible factor-1α (HIF1-α) and aryl hydrocarbon receptor (AHR) supports the differentiation of type 1 regulatory (Tr1) cells. HIF1-α controls the early metabolic reprograming of Tr1 cells. At later time points, AHR promotes HIF1-α degradation and takes control of Tr1 cell metabolism. Extracellular adenosine triphosphate (eATP) and hypoxia, linked to inflammation, trigger AHR inactivation by HIF1-α and inhibit Tr1 cell differentiation. Conversely, CD39 promotes Tr1 cell differentiation by depleting eATP. CD39 also contributes to Tr1 suppressive activity by generating adenosine in cooperation with CD73 expressed by responder T cells and antigen presenting cells. These results suggest that HIF1-α and AHR integrate immunological, metabolic and environmental signals to regulate the immune response.

A major goal of immunotherapy for autoimmune diseases and transplantation is induction of regulatory T cells that mediate immunologic tolerance. The mucosal immune system is unique, as tolerance is preferentially induced after exposure to antigen, and induction of regulatory T cells is a primary mechanism of oral tolerance. Parenteral administration of CD3-specific monoclonal antibody is an approved therapy for transplantation in humans and is effective in autoimmune diabetes. We found that orally administered CD3-specific antibody is biologically active in the gut and suppresses autoimmune encephalomyelitis both before induction of disease and at the height of disease. Orally administered CD3-specific antibody induces CD4+ CD25- LAP+ regulatory T cells that contain latency-associated peptide (LAP) on their surface and that function in vitro and in vivo through a TGF-beta-dependent mechanism. These findings identify a new immunologic approach that is widely applicable for the treatment of human autoimmune conditions.

Multiple sclerosis (MS) is a chronic relapsing disease of the central nervous system (CNS) in which immune processes are believed to play a major role. To date, there is no reliable method by which to characterize the immune processes and their changes associated with different forms of MS and disease progression. We performed antigen microarray analysis to characterize patterns of antibody reactivity in MS serum against a panel of CNS protein and lipid autoantigens and heat shock proteins. Informatic analysis consisted of a training set that was validated on a blinded test set. The results were further validated on an independent cohort of relapsing-remitting (RRMS) samples. We found unique autoantibody patterns that distinguished RRMS, secondary progressive (SPMS), and primary progressive (PPMS) MS from both healthy controls and other neurologic or autoimmune driven diseases including Alzheimer's disease, adrenoleukodystropy, and lupus erythematosus. RRMS was characterized by autoantibodies to heat shock proteins that were not observed in PPMS or SPMS. In addition, RRMS, SPMS, and PPMS were characterized by unique patterns of reactivity to CNS antigens. Furthermore, we examined sera from patients with different immunopathologic patterns of MS as determined by brain biopsy, and we identified unique antibody patterns to lipids and CNS-derived peptides that were linked to each type of pathology. The demonstration of unique serum immune signatures linked to different stages and pathologic processes in MS provides an avenue to monitor MS and to characterize immunopathogenic mechanisms and therapeutic targets in the disease.antibodies ͉ autoimmunity ͉ biomarker

Axonal degeneration is an important determinant of progressive neurological disability in multiple sclerosis (MS).

Adipose-derived mesenchymal stem cells (ADMSCs) display immunosuppressive properties, suggesting a promising therapeutic application in several autoimmune diseases, but their role in type 1 diabetes (T1D) remains largely unexplored. The aim of this study was to investigate the immune regulatory properties of allogeneic ADMSC therapy in T cell–mediated autoimmune diabetes in NOD mice. ADMSC treatment reversed the hyperglycemia of early-onset diabetes in 78% of diabetic NOD mice, and this effect was associated with higher serum insulin, amylin, and glucagon-like peptide 1 levels compared with untreated controls. This improved outcome was associated with downregulation of the CD4+ Th1-biased immune response and expansion of regulatory T cells (Tregs) in the pancreatic lymph nodes. Within the pancreas, inflammatory cell infiltration and interferon-γ levels were reduced, while insulin, pancreatic duodenal homeobox-1, and active transforming growth factor-β1 expression were increased. In vitro, ADMSCs induced the expansion/proliferation of Tregs in a cell contact–dependent manner mediated by programmed death ligand 1. In summary, ADMSC therapy efficiently ameliorates autoimmune diabetes pathogenesis in diabetic NOD mice by attenuating the Th1 immune response concomitant with the expansion/proliferation of Tregs, thereby contributing to the maintenance of functional β-cells. Thus, this study may provide a new perspective for the development of ADMSC-based cellular therapies for T1D.

Beta2-adrenergic receptor (B2AR) signaling is known to impairKeywords: Foxp3 · Noradrenaline · Sympathetic nervous system · Treg cell Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionLymphoid organs such as the spleen and the lymph nodes are richly innervated by the sympathetic nervous system (SNS), especially within T-cell areas [1]. Immune responses can be moduCorrespondence: Dr. Alexandre S. Basso e-mail: asbasso@unifesp.br lated by catecholamines released upon sympathetic activity only if immune cells are able to respond to them by expressing functional catecholaminergic receptors. Indeed, the beta2-adrenergic receptor (B2AR) has been described as the main adrenergic receptor expressed in immune cells, including dendritic cells, macrophages, CD4 + T cells, CD8 + T cells, and B cells [2,3]. Furthermore, increased noradrenaline release in the spleen followed by the activation of antigen-specific T and B cells has been already reported, indicating that an adaptive immune response can lead to enhanced SNS activity within lymphoid organs [4]. Taken 1002 Marcia. G. Guereschi et al. Eur. J. Immunol. 2013. 43: 1001-1012 sympathetic innervation of lymphoid organs, SNS activation due to adaptive immune responses, and the expression of adrenergic receptors by immune cells build a solid case supporting the concept that the SNS represents a feedback mechanism that is able to modulate immune responses [5]. Thus far, it has been shown that B2AR is expressed in CD4 + naïve T cells and Th1 clones while it is completely absent in Th2 clones [3,6]. CD4 + T-cell stimulation along with B2AR activation decreased IL-2 production and IL-2 receptor α-chain (CD25) expression in a cAMP-dependent way [3,[6][7][8]. Activation of Th1 clones in the presence of a B2AR agonist may also impair IL-2 and IFN-γ expression [6,7]. Furthermore, by selective inhibition of IL-12 production in LPS-stimulated human dendritic cells, B2AR agonists were found to block in vitro differentiation of neonatal CD4 + T cells into IFN-γ-producing cells, favoring IL-4 production instead [9]. Therefore information on SNS-mediated modulation of CD4 + T-cell immune responses via B2AR activation has been concentrated on the dichotomy Th1/Th2; and in general these data point to a role for B2AR activation in inhibiting the development of Th1 responses [6,8,9]. Very little is known on how adrenergic neurotransmitters could modulate the activity of other CD4 + T-cell subsets, among them Foxp3− T cells possess transcripts for the beta1-adrenergic receptor (B1AR) and the alpha2A-adrenergic receptor (A2aAR), besides the B2AR (Supporting Information Fig. 1A). Among those three, the B2AR is far more expressed than the other two (Supporting Information Fig. 1A). that Treg cells also express the B2AR, the B1AR, and the A2aAR (Supporting Information Fig. 1B). In Treg cells, B2AR was also expressed at higher levels as compared to B1AR and A2aAR (Supporting Information Fig. 1B). When comparing B2AR mRN...

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