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ZUSAMMENFASSUNGDie umfassende Erforschung der Immunologie des Typ-1-Diabetes kann entscheidend zu unserem Verständnis der Krankheit beitragen. Hierbei ist insbesondere auch die Identifizierung der zugrundeliegenden Signalwege, die zur fehlerhaften Immuntoleranz sowie der Aktivierung und dem Fortschreiten der Inselautoimmunität beitragen, von entscheidender Bedeutung für die Entwicklung zukünftiger Interventionsstrategien, um die Entstehung von Typ-1-Diabetes zu verlangsamen oder sogar ganz zu verhindern 1. So bieten kürzlich identifizierte miRNAs, die zur Entstehung von Inselautoimmunität beitragen, einen vielversprechenden Ansatz, um Treg-vermittelte Toleranzdefekte mittels gezielter miRNA-Modulation zu reduzieren.

The development of multiple disease-relevant autoantibodies is a hallmark of autoimmune diseases. In autoimmune type 1 diabetes (T1D), a variable time frame of autoimmunity precedes the clinically overt disease. The relevance of T follicular helper (TFH) cells for the immune system is increasingly recognized. Their pivotal contribution to antibody production by providing help to germinal center (GC) B cells facilitates the development of a long-lived humoral immunity. Their complex differentiation process, involving various stages and factors like B cell lymphoma 6 (Bcl6), is strictly controlled, as anomalous regulation of TFH cells is connected with immunopathologies. While the adverse effects of a TFH cell-related insufficient humoral immunity are obvious, the role of increased TFH frequencies in autoimmune diseases like T1D is currently highlighted. High levels of autoantigen trigger an excessive induction of TFH cells, consequently resulting in the production of autoantibodies. Therefore, TFH cells might provide promising approaches for novel therapeutic strategies.

Obesity and type 2 diabetes are associated with metabolic defects and adipose tissue inflammation. Foxp3(+) regulatory Tcells (Tregs) control tissue homeostasis by counteracting local inflammation. However, if and how Tcells interlink environmental influences with adipocyte function remains unknown. Here, we report that enhancing sympathetic tone by cold exposure, beta3-adrenergic receptor (ADRB3) stimulation or a short-term high-calorie diet enhances Treg induction invitro and invivo. CD4(+) Tcell proteomes revealed higher expression of Foxp3 regulatory networks in response to cold or ADRB3 stimulation invivo reflecting Treg induction. Specifically, Ragulator-interacting protein C17orf59, which limits mTORC1 activity, was upregulated in CD4(+) Tcells by either ADRB3 stimulation or cold exposure, suggesting contribution to Treg induction. By loss- and gain-of-function studies, including Treg depletion and transfers invivo, we demonstrated that a Tcell-specific Stat6/Pten axis links cold exposure or ADRB3 stimulation with Foxp3(+) Treg induction and adipose tissue function. Our findings offer a new mechanistic model in which tissue-specific Tregs maintain adipose tissue function.