Lymphotoxin alpha fine-tunes T cell clonal deletion by regulating thymic entry of antigen-presenting cells

Medullary thymic epithelial cells (mTEC) purge the T cell repertoire of autoreactive thymocytes. Although dendritic cells (DC) reinforce this process by transporting innocuous peripheral self-antigens, the mechanisms that control their thymic entry remain unclear. Here we show that mTEC-CD4(+) thymocyte crosstalk regulates the thymus homing of SHPS-1(+) conventional DCs (cDC), plasmacytoid DCs (pDC) and macrophages. This homing process is controlled by lymphotoxin alpha (LT alpha), which negatively regulates CCL2, CCL8 and CCL12 chemokines in mTECs. Consequently, Lt alpha-deficient mice have increased expression of these chemokines that correlates with augmented classical NF-kappa B subunits and increased thymic recruitment of cDCs, pDCs and macrophages. This enhanced migration depends mainly on the chemokine receptor CCR2, and increases thymic clonal deletion. Altogether, this study identifies a fine-tuning mechanism of T cell repertoire selection and paves the way for therapeutic interventions to treat autoimmune disorders