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Nicolas S Merle, Martin Kolev, Jubayer Rahman, Erin West, Bingyu Yan, Majid Kazemian, Behdad Afzali, Claudia Kemper, The C3-like molecule CD109 controls Th1 versus Th17 induction in CD4+ T cells, The Journal of Immunology, Volume 204, Issue 1_Supplement, May 2020, Page 150.4, https://doi.org/10.4049/jimmunol.204.Supp.150.4
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Abstract
Recent work defined an unexpected and critical role for intracellular/autocrine active complement in human Th1 biology. Specifically, autocrine stimulation of CD46 via TCR-induced C3b generation is needed for IFN-γ production by human CD4+T cells. Analysis of the CD46-driven gene signature in Th1 cells revealed CD109, a C3-like surface protein known to regulate TGF-β signaling, as a direct target of CD46. We confirmed that T cells from patients with CD46 deficiency, which suffer from recurrent infection due to reduced Th1 responses, and from healthy donors knocked-out for CD46 via CRISPR-Cas9 technology failed to upregulate CD109. CD109 is expressed on keratinocytes, endothelial and stem cells and overexpression is connected with cancer but its function on T cells remains unexplored.
In vitro activation of mouse Cd109−/− CD4+ T-cells showed a strong increase of Th1- and Th17-related cytokines compare to their WT counterpart. In line with this observation, Cd109−/− mouse CD4+ T cells showed an increase in IL-17A+ and IFN-γ+/IL-17A+ T cell numbers in vivo and caused significantly more weight loss and disease pathology in a T cell-transfer colitis model. Although CD109 is known to regulate TGF-β signaling, our RNA-sequencing analysis of activated Cd109−/− mouse T cells revealed that this molecule is restraining Th17 induction rather via impact on cell cycle and apoptosis related pathways, which we are investigating now.
Together, these data suggest that the complement-related protein CD109 serves as an important and novel molecular switch on CD4+ T-cells, where it regulates the balance between Th1 and Th17-induction pathways.
