Meet the lab

Translational Complement Research

Kemper Lab Member
Kemper Lab

Complement is undeniably quintessential for innate immunity by detecting and eliminating infectious microorganisms. We have highlighted an equally profound impact of complement on adaptive immunity through direct regulation of CD4+ T cells: signals mediated by T cell-expressed anaphylatoxin receptor C3aR and the complement regulator CD46 (which binds the complement activation fragment C3b) are critical checkpoints in human T cell lineage commitment and control initiation and resolution of inflammatory Th1 responses (Kemper, Nature, 2003; Cardone, Nat Immunol., 2010; Le Friec, Nat Immunol., 2012). Mechanistically, CD46-mediated signals initially drive the assembly of the IL-2R on the T cell surface and later, after expansion of protective Th1 responses, induce the co-production of immunosuppressive IL-10 within Th1 cells and their ‘switch’ into a (self)regulatory and contracting phenotype (Cardone et al., Nat Immunol, 2010). Further, we have discovered that activation of the key complement components C3 and C5 is not confined to the extracellular space but occurs intracellulary (the ‘Complosome’) and that intracellular C3 and C5 activation fundamentally dictates the magnitude of Th1-mediated inflammation (Liszewski, Immunity, 2013). Consequently, lack of autocrine complement activation by T cells results in deficient Th1 responses and recurrent infections (Ghannam et al., Mol Immunol, 2014), while uncontrolled intracellular C3 and/or C5 activation contributes to hyperactive Th1 responses observed in autoimmunity (rheumatoid arthritis, CAPS) and can be normalised pharmacologically by inhibiting intracellular complement activity (Kolev, Nat Rev Immunol, 2014; Arbore, Science, 2016). 

Likely the most exciting recent development in our work is the observation that intracellular C3 and C5 are critical for the homeostatic survival of T cells (through intracellular tonic C3aR activation) and for metabolic reprogramming during cell activation via CD46-driven induction of glycolysis and oxidative phosphorylation (Kolev, Immunity, 2015) and C5-mediated increases in oxygen metabolism (Arbore, Science, 2016). Thus, complement plays unexpectedly a fundamental role in basic processes of the cell (Figure 1) and understanding these novel functions will deliver critical new knowledge about T cell biology in health and disease.

The central goal of our research programme is therefore to define the functional novel and non-canonical roles and regulative mechanisms of intracellular/autocrine complement and assess their biological relevance with an eye on delivering druggable targets in these pathways to therapeutically intervene in (autoimmune) diseases.