The Pieters Laboratory—Research/Projects
The Coronin Pathway: An evolutionarily conserved pathway that defines cell population size
Maintenance of cell population size, such as for circulating T cells, is fundamental to the proper functioning of multicellular organisms. Our research revealed coronin proteins as key controllers of cell population size by regulating a cell-intrinsic cell density–sensing pathway enabling cells to reach and maintain an appropriate population size. This pathway operates “kin-to-kin” or between identical or similar cell populations. We showed that in T cells, coronin 1 coordinates pro-survival signaling with the inhibition of cell death until the cell population reaches threshold densities. At or above threshold densities, coronin 1 expression peaks and remains stable, thereby resulting in the initiation of apoptosis through kin-to-kin intercellular signaling to return the cell population to the appropriate cell density. We found that this cell population size-controlling pathway is conserved from amoeba to humans, thus providing evidence for the existence of a coronin-regulated, evolutionarily conserved mechanism by which cells are informed of and coordinate their relative population size (Nindyanka Fabrice et al., Science signaling (2022)).
Unravelling the molecular mechanisms underlying coronin-regulated cell density sensing and cell population size regulation
Our current and future efforts are and will be directed towards a molecular understanding of how the coronin signaling pathway controls cell population size. For example, mammals express up to seven coronin genes, some of which are expressed ubiquitously, whereas others are expressed in a more restricted and tissue-specific manner. We are establishing experimental systems and approaches, making use of gene editing, cell culture systems and different ex vivo and in vivo models that we combine with state-of-the art proteomics, transcriptomics, biochemistry and imaging to analyze the roles for the different coronin proteins in the control of cell population size and density sensing.
Model depicting the role for coronin 1/A in cell population homeostasis and maintaining cellular individuality
Upper panel: During cell population increase, coronin 1/A expression (green) is tuned to cell density increase, thereby dampening adhesin-initiated cell population growth arrest and/or death signaling (red). Lower left: Whereas at low cell densities, coronin is dispensable for cell population density increase, in its absence the threshold at which growth arrest/death signaling is initiated is far below the threshold at which wild type cells regulate their cell density. Lower right: This role for coronin 1/A to coordinate kin-to-kin sensing with cell population density also allows the maintenance of cellular individuality. See Nindyanka Fabrice et al., 2022.
A coronin 1-dependent signaling pathway specifically involved in auto- and allo-immune responses and dispensable for immunity against pathogenic infections
We recently demonstrated that disruption of coronin 1 signaling promotes tolerance towards autoimmune triggers and allografts, in the absence of immunosuppression-associated co-morbidities. The ability to specifically suppress allo- and autoimmune responses has also been referred to as the ‘holy grail’ for achieving immune tolerance, see also Jayachandran et al., Immunity (2019). Mechanistically, we found that coronin 1-deficiency modulated cAMP concentrations to suppress allo-specific T cell responses without compromising pathogen-specific immunity. Within this research, our efforts are directed towards uncovering the molecular differences involved in allo/autoimmune versus antipathogen responses, as well as develop strategies to specifically target the coronin 1 and allo/auto immune-selective pathway.