Lymphotoxin α 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 α (LTα), which negatively regulates CCL2, CCL8 and CCL12 chemokines in mTECs. Consequently, Ltα-deficient mice have increased expression of these chemokines that correlates with augmented classical NF-κB 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.

PTBP1 is necessary for dendritic cells to regulate T‐cell homeostasis and antitumour immunity

“…In the steady state, DCs also maintain immune tolerance. It has been proposed that DCs may directly present or cross‐present self‐Ags for negative selection of thymocytes 54 . In addition, peripheral DCs may recirculate into the thymus and induce clonal deletion of T cells and Treg proliferation 55 .…”

“…54 In addition, peripheral DCs may recirculate into the thymus and induce clonal deletion of T cells and Treg proliferation. 55 Nevertheless, complete deletion of DCs does not influence the peripheral T-cell repertoire, indicating that DCs do not play a dominant role in peripheral immune tolerance. 8 In our experiments, we found that Ptbp1 deletion could perturb T-cell homeostasis without affecting T-cell development.…”

The Regulatory Function of CCR9+ Dendritic Cells in Inflammation and Autoimmunity

“…It has been reported that CCR7 drives the recruitment of cDCs in the thymus as Ccr7 -/- , Ccl21a -/- , or Ccl19 -/- mice that show a defect in the migration of cDC progenitors ( 39 ). CCL2/CCR2 interaction helps in the migration of cDCs into the thymic cortex and localizing them to perivascular spaces where they further participate in central tolerance by depleting autoreactive T cell clones ( 36 , 38 , 40 ). This homing process is also controlled by lymphotoxin α (LTα), which negatively regulates CCL2, CCL8, and CCL12 chemokines in the thymus ( 40 ).…”

“…CCL2/CCR2 interaction helps in the migration of cDCs into the thymic cortex and localizing them to perivascular spaces where they further participate in central tolerance by depleting autoreactive T cell clones ( 36 , 38 , 40 ). This homing process is also controlled by lymphotoxin α (LTα), which negatively regulates CCL2, CCL8, and CCL12 chemokines in the thymus ( 40 ). CCL8 is also a ligand for CCR1 and CCR5 and involved in the migration of pDCs and cDCs in the thymus ( 40 ).…”

“…This homing process is also controlled by lymphotoxin α (LTα), which negatively regulates CCL2, CCL8, and CCL12 chemokines in the thymus ( 40 ). CCL8 is also a ligand for CCR1 and CCR5 and involved in the migration of pDCs and cDCs in the thymus ( 40 ). Our recent study also suggests that CD103 + DCs and thymic DCs are a potent inducer of Treg in the presence of CCL25 ( 14 ).…”