Our laboratory aims at understanding the unexpected roles of complement in the regulation of key basic processes of the cell in health and disease.
Complement is generally well appreciated as a serum-effective system and critical arm of innate immunity required for the detection and removal of invading pathogens. Recent work from Dr. Kemper's lab, however, has 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. Further, they 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. Consequently, lack of autocrine complement activation by T cells results in deficient Th1 responses and recurrent infections, 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.
Likely the most exciting recent development in their 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 nutrient influx, mTORC1 assembly and glycolysis and oxidative phosphorylation, and C5-mediated increases in oxygen metabolism. Importantly, although intially discovered in T cells, these Complosome-regulated pathways seem to operate in a broad range of cells.
Thus, complement plays unexpectedly a fundamental role in basic processes of the cell and understanding these novel functions will deliver critical new knowledge about cell biology in health and disease.
The central goal of Dr. Kemper's research programme is therefore to define the functional 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. To achieve this overarching goal, Dr. Kemper's lab are currently focusing on three key questions:
1. What is the composition of the Complosome in different cells?
2. What are the functions of the Complosome?
3. How is the Complosome regulated?
They utilize immune/tissue cells from healthy donors, from patients with complement deficiencies, from patients with T cell-driven autoimmune disease and from patients with deviations in novel ‘complosome’-regulated pathways for gene and miRNA arrays, epigenetic landscape evaluation, and proteomic and metabolomic assessments. This unbiased approach driven by human genetics and robust experimental in vitro systems will be combined with appropriate small animal (mouse) in vivo models to define biological significance of proteins/pathways discovered and to develop preclinical animal models for future pharmacological targeting.