Le stress protéotoxique : le prix à payer pour la tolérance au soi immunitaire
In all vertebrates, the thymus is the sole site where hematopoietic progenitors develop into functionally competent T cells. Notably, the thymus ages more rapidly than other organs because of a progressive loss of medullary thymic epithelial cells (mTECs). This so-called thymic involution increases the susceptibility to infections and autoimmune diseases and impairs response to vaccines and cancer immunosurveillance. Thus, the objective of this thesis was to elucidate the mechanisms controlling mTEC homeostasis in vivo, which would greatly facilitate the rational design of novel strategies for reversing thymic involution and ultimately, rejuvenate the immune system. The sole non-redundant role of mTECs is to induce self tolerance, a vital process that depends on a unique feature of mTECs: promiscuous gene expression (pGE). We found that, because of pGE, mature mTECs can collectively express almost the entire repertoire of known protein-coding genes and thereby induce tolerance to most antigens expressed in the organism. While pGE is the key process enabling mTECs to establish self-tolerance, our results show that the price to pay for pGE is an increased protein biogenesis and higher susceptibility to proteotoxic stress in mature mTECs, which need immunoproteasomes (IPs) to mitigate this stress. Notably, we found that IP-deficiency leads to exhaustion of postnatal mTEC progenitors and that IP-deficient mice show accelerated thymic involution and multiorgan autoimmune manifestations. Taken together, our work identifies IPs as major regulators of mTEC homeostasis and provides a potential biological target for reversing age-dependent thymic atrophy.
Thymus Thymic epithelial cells Thymic involution Self-tolerance Promiscuous gene expression Immunoproteasome Proteotoxic stress Autoimmunity