The role of the intracellular complement system - the complosome - in Th1 biology

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We aim at understanding the role of the complosome in both initiation (IFN-gamma production) and contraction (IL-10 switching) of human Th1 responses as well as CD8+ CTL biology. A. We have made major progress in understanding how C3 gene expression is regulated in T and other immune cells. We found that signals mediated by the integrin LFA-1 (engaged during diapedesis of immune cells into tissues) is a master inducer of C3. In consequence, patients with deficiency in LFA-1 cannot upregulate C3 in immune cells and, thus, lack normal Th1, CTL and IL-1b producing macrophages (Kolev and West, Immunity, 2020). B. We have now also been able to detangle the exact molecular mechanisms by which the intracellular domain of CD46 induces Th1-related genes and activities in human CD4+ T cells. This occurs via direct interaction with certain metabolic enzymes in the cytosol as well as via interaction with specific transcription factors in the nucleus (manuscripts in preparation). C. We have made equal progress in understanding how the complosome co-induces IL-10 in Th1 cells and initiates their shutdown program. These novel functions of the complosome involve the controlled expression induction of metabolic enzymes regulating lipid and amino acid usage (manuscripts in preparation). D. In an attempt to understand the signaling event underlying naive and memory CD4+ and CD8+ T cell activation in unprecedented depth, we have performed the first comparative scRNA-seq analysis of human sorted T cells over time and analyzed the data utilizing a novel algorithm integrating multiple unknown multivariate probability distributions in collaboration with the Zhang laboratory at U-Penn (manuscript in preparation).