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

ABSTRACT: 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 ? (LT?), which negatively regulates CCL2, CCL8 and CCL12 chemokines in mTECs. Consequently, Lt?-deficient mice have increased expression of these chemokines that correlates with augmented classical NF-?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.

SUBMITTER: Lopes N 

PROVIDER: S-EPMC5872006 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature