Thymic exosomes - effects on selection and maturation of thymocytes

Abstract

T cell tolerance is primarily shaped in the thymus, through direct and indirect presentation of self-antigens to developing T cells. Medullary thymic epithelial cells (mTECs), producing and expressing self-antigens, together with dendritic cells (DCs) are the key antigen presenting cells in the thymus. In addition to direct presentation of self-antigens by mTECs, antigens are transferred to DCs followed by presentation to developing thymocytes. The underlying mechanism of this antigen transfer is not understood. Extracellular vesicles (EVs), and more specifically exosomes, are known to carry antigens and genomic material with a biological function to target cells. This thesis report thymic exosomes as mediators of antigen transfer important for T cell maturation, negative selection and Treg development. Furthermore, we show that thymic exosomes carry co-stimulatory molecules and MHC II. In the first paper, we report that exosomes derived from primary human thymic epithelial cell cultures carry self-antigens associated with autoimmune diseases. The second paper demonstrates how exosomes from mouse thymic tissue induce the final maturation of thymocytes, independently of antigen presenting cells (APCs), before they egress the thymus as T cells, in vitro. In order to study the impact of thymic exosomes on central tolerance in vivo, we used the transgenic mouse model insHEL-3A9 TCR, which is well described in studies of central tolerance. We report that thymic exosomes from HEL-mice carry the dominant HEL-peptide in complex with MHC II on their surface. Injection of thymic exosomes from HEL-mice into 3A9 TCR mice resulted in a reduction of HEL-specific thymocytes and expansion of peripheral Tregs, suggesting that thymic exosomes are important for tolerance induction. In conclusion, this thesis reports that thymic exosomes carry self-antigens and are mediators for the induction of central and peripheral tolerance.