Lymphotoxin \u03b1 fine-tunes T cell clonal deletion by regulating thymic entry of antigen-presenting cells

Noëlla Lopes,Magali Irla,Arnauld Sergé,Jonathan Charaix,Oriane Cédile

doi:10.1038/s41467-018-03619-9

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.

Highlights

To cite this version: Noella Lopes, Jonathan Charaix, Oriane Cédile, Arnauld Sergé, Magali Irla
To investigate whether interactions between Medullary thymic epithelial cells (mTEC) and autoreactive CD4+ thymocytes regulate the intrathymic pool of dendritic cells (DC) and macrophages, we used OTII-Rag2−/− and RipmOVA-Rag2−/− recipients (OTII)-Rag2−/− mice, which express a MHCII-restricted transgenic TCR specific for ovalbumin (OVA), and RipmOVAxOTII-Rag2−/− mice, carrying a RipmOVA transgene that drives the synthesis of membrane-bound OVA in mTECs
We found an ~1.5–3-fold increase in frequencies and numbers of CD11chiBST-2lo conventional DCs (cDC) and CD11cintBST-2hi plasmacytoid DCs (pDC) from RipmOVAxOTII-Rag2−/− compared with OTII-Rag2−/− thymi (Fig. 1a, Supplementary Fig. 1)

Summary

Introduction

To cite this version: Noella Lopes, Jonathan Charaix, Oriane Cédile, Arnauld Sergé, Magali Irla. HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. 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. 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. DCs are involved in the deletion of both DP thymocytes in the cortex and SP thymocytes in the medulla[10] They constitute a heterogeneous population comprising three distinct subsets: CD11cintBST-2hi plasmacytoid DCs (pDC) and two CD11chi conventional DC (cDC) subsets—CD11chiCD8αhiSHPS-1− resident and CD11chiCD8αloSHPS-1+ migratory cDCs11,12. Migratory cDCs and pDCs reinforce the deletion of autoreactive thymocytes by continuously migrating from the blood to the thymus, where they display peripheral self-Ags that would be otherwise not presented to thymocytes[17,18,19,20,21]

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Results

Conclusion