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Innate signals regulating the Th1 cell life cycle

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Control of IFN -g-secreting T helper (Th) 1 cells is vital for the prevention of autoimmunity and immunopathology during infection. The cytokine interleukin (IL)-10 is fundamental in the negative control of Th1 cells. IL-10-mediated Th1 regulation is achieved ‘extrinsically’ through suppression by induced IL-10-secreting regulatory T cells (iTreg or Tr1) and ‘intrinsically’ by a recently discovered negative feedback loop working via the timely co-induction of IL-10 in addition to IFN -g during Th1 lineage differentiation. We identified the complement regulator CD46 as key receptor in regulating IFN -g and IL-10 production in TH1 cells. CD46 not only drives IFN -g production and effector function of human TH1 cells but also induces the switch to IL-10 secretion and into the regulatory phase in an IL-2-dependent fashion: In the presence of low IL-2 CD46 induces almost exclusively IFN -g+ effector TH1 cells while high environmental IL-2 then switches these cells from an IFN -g+/IL-10+ intermediate finally into IL-10+ T cells, with both of the latter populations being suppressive. Importantly, this CD46 -mediated switch is defective in rheumatoid arthritis (RA) patients: T cells from these patients lack the IL-10+ cell subpopulation, produce up to 20 times more IFN -g compared to those from healthy individuals and never enter the regulatory phase. Thus, we hypothesize that innate CD46 -transduced signals play a vital role in the induction and resolution of human TH1 responses and that disturbance in CD46 signals is associated with autoimmune disease states including at minimum RA. Inducing/abrogating IFN -γ to IL-10 switching in Th1 cells at will presents one of the most tantalising prospects for developing novel therapeutics targeting Th1-mediated diseases – here will summarize our present knowledge of the innate-driven molecular pathways regulating the expression of IFN -γ vs. IL-10 in Th1.

This talk is part of the Departmental Seminar Programme, Department of Veterinary Medicine series.

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