Defining the role of CCR8 in promoting thymocyte development and thymic epithelial homeostasis

Abstract

Abstract Generation of functional and self-tolerant T cells in the thymus is crucial to preventing autoimmune diseases. Medullary thymic epithelial cells (mTECs) and dendritic cells (DCs) present diverse auto-antigens to developing thymocytes; strong TCR reactivity in response to self-antigens causes thymocytes to undergo negative selection, eliminating autoreactive cells from the repertoire. Chemokine receptors expressed on the surface of developing thymocytes have been shown to promote accumulation of post-positive selection thymocytes in the medulla, where they may encounter mTECs and DCs presenting auto-antigens. CCR8 is highly expressed by post-positive selection CD4 thymocytes while its ligands, CCL1 and CCL8 are expressed by mTECs. Thus, CCR8 signaling may promote medullary entry of post-positive selection thymocytes and efficient interactions with mTECs and enforcing central tolerance. Our preliminary data indicate that CCR8−/− thymi have a reduced medullary area, implicating impaired thymocyte:mTEC interactions that impacts normal proliferation and differentiation of mTECs. Furthermore, 2-photon imaging reveals that CCR8 deficiency results in a significant increase in the path straightness of CD4 SP thymocytes, which could impact the efficiency of interactions with medullary stromal cells. Strikingly, CCR8 deficiency results in increased cellularity of CD4SP OTII TCR transgenic thymocytes in a wild-type host, suggesting CCR8 is critical for efficient clonal deletion to endogenous auto-antigens. Thus, our preliminary data indicate that CCR8 contributes to the migratory properties and stromal interactions of post-positive selection thymocytes that promote efficient negative selection.