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CD83 orchestrates immunity towards self and non-self in dendritic cells

Wild, AB;Krzyzak, L;Peckert, K;Stich, L;Kuhnt, C;Butterhof, A;Seitz, C;Mattner, J;Grner, N;Gnsbauer, M;Purtak, M;Soulat, D;Winkler, TH;Nitschke, L;Zinser, E;Steinkasserer, A;

Dendritic cells (DCs) are crucial to balance protective immunity and autoimmune inflammatory processes. Expression of CD83 is a well-established marker for mature DCs although its physiological role is still not completely understood. Using a DC-specific CD83 conditional KO mouse (CD83DC) we provide new insights into the function of CD83 within this cell type. Interestingly, CD83-deficient DCs produced drastically increased IL-2 levels and displayed higher expression of the co-stimulatory molecules CD25 and OX40L, which causes superior induction of antigen-specific T cell responses and compromises Treg suppressive functions. This also directly translates into accelerated immune responses in vivo. Upon Salmonella typhimurium and Listeria monocytogenes infection, CD83DC mice cleared both pathogens more efficiently, and CD83-deficient DCs expressed increased IL-12 levels after bacterial encounter. Using the experimental autoimmune encephalomyelitis (EAE) model, autoimmune inflammation was dramatically aggravated in CD83DC mice, while resolution of inflammation was strongly reduced. This phenotype was associated with increased cell influx into the CNS accompanied by elevated Th17 cell numbers. Concomitantly, CD83DC mice had reduced Treg numbers in peripheral lymphoid organs. In summary, we show that CD83 ablation on DCs results in enhanced immune responses by dysregulating tolerance mechanisms and thereby impairing resolution of inflammation, which also demonstrates high clinical relevance.