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

National Heart, Lung, And Blood Institute

Investigators

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Abstract

The Complement and Inflammation Research Section (CIRS) focusses on the role of cell-autonomous in health and disease, with a specific focus on complement-driven inflammation in autoimmunity (arthritis) and cardiovascular disease. 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 specific transcription factors in the nucleus (manuscript 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 (manuscript submitted and 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 (Bibby et al., Cell Reports, 2022). E. We have now also shown that CD46 controls glutamine and arginine influx into T cells and via subsequent control of arginase 1 activity the Th1 shutdown program (West et al., Immunity, 2023) as well as having identified C5 as a novel regulator of prostanoid metabolism (Rahman et al., Immunity, 2025). F. Trying to move towards modulating cell autonomous complement actively in human disease, we have identified T cell autonomous complement as the top induced pathways in regulatory T cells in individuals with CVD and that have been treated with low dose IL-2 (Case et al., Nat Cardiov. Res, 2025). We are are currently aiming at identifying the complement-mediated pathways that respond to IL-2 and alter T cell behavior.