DOCK8 regulates fitness and function of regulatory T cells through modulation of IL-2 signaling


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Singh A. K. , Eken A. , Hagin D., Komal K., Bhise G., Shaji A., ...Daha Fazla

JCI INSIGHT, cilt.2, 2017 (SCI İndekslerine Giren Dergi) identifier identifier

Özet

Foxp3+ regulatory T (Treg) cells possess potent immunosuppressive activity, which is critical for maintaining immune homeostasis and self-tolerance. Defects in Treg cell development or function result in inadvertent immune activation and autoimmunity. Despite recent advances in Treg cell biology, we still do not completely understand the molecular and cellular mechanisms governing the development and suppressive function of these cells. Here, we have demonstrated an essential role of the Dedicator of cytokinesis 8 (DOCK8), guanine nucleotide exchange factors required for cytoskeleton rearrangement, cell migration and immune cell survival, in controlling Treg cell fitness and their function. Treg cell-specific DOCK8-deletion led to spontaneous multi-organ inflammation in mice due to uncontrolled T cell activation and production of pro-inflammatory cytokines. In addition, we show that DOCK8-deficient Treg cells are defective in competitive fitness and in vivo suppressive function. Furthermore, DOCK8 controls IL-2 signaling, crucial for maintenance and competitive fitness of Treg cells, via a STAT5-dependent manner. Our study provides novel insights into the essential function of DOCK8 in Treg cells and immune regulation, and explains the autoimmune manifestations associated with DOCK8-deficiency.