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

Noëlla Lopes, Jonathan Charaix, Oriane Cédile, Arnauld Sergé and Magali Irla ()
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Noëlla Lopes: INSERM U1104, CNRS UMR7280, Aix-Marseille Université UM2
Jonathan Charaix: INSERM U1104, CNRS UMR7280, Aix-Marseille Université UM2
Oriane Cédile: University of Southern Denmark
Arnauld Sergé: Institut Paoli-Calmettes, INSERM U1068, CNRS UMR7258, Aix-Marseille Université UM105
Magali Irla: INSERM U1104, CNRS UMR7280, Aix-Marseille Université UM2

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03619-9

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