Glycosyltransferase Extl1 promotes CCR7-mediated dendritic cell migration to restrain infection and autoimmunity

Juan Liu; Yujie Cheng; Xiaomin Zhang; Yali Chen; Ha Zhu; Kun Chen; Shuxun Liu; Zhiqing Li; Xuetao Cao

doi:10.1016/j.celrep.2023.111991

Glycosyltransferase Extl1 promotes CCR7-mediated dendritic cell migration to restrain infection and autoimmunity

Cell Rep. 2023 Jan 31;42(1):111991. doi: 10.1016/j.celrep.2023.111991. Epub 2023 Jan 18.

Authors

Juan Liu¹, Yujie Cheng², Xiaomin Zhang², Yali Chen³, Ha Zhu², Kun Chen³, Shuxun Liu², Zhiqing Li², Xuetao Cao⁴

Affiliations

¹ National Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical University, Shanghai 200433, China. Electronic address: juanliu@immunol.org.
² National Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
³ Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China.
⁴ National Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical University, Shanghai 200433, China; Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China; Frontier Research Center for Cell Response, Institute of Immunology, College of Life Sciences, Nankai University, Tianjin 300071, China. Electronic address: caoxt@immunol.org.

PMID: 36656709
DOI: 10.1016/j.celrep.2023.111991

Abstract

CCR7-triggered DC migration toward draining lymph nodes is critical for the initiation of protective immunity and maintenance of immune tolerance. How to promote CCR7-mediated DC migration to determine T cell responses under inflammatory and homeostatic conditions remains poorly understood. Here we demonstrate that the Extl1 (Exostosin like glycosyltransferase 1) promotes CCR7-triggered DC migration in a heparan sulfate proteoglycans (HSPG)-dependent manner. Mechanistically, Extl1 mediates HSPG production via its glycosyltransferase domain to inhibit C1q expression. Extl1/HSPG axis relieves C1q-mediated restriction of CCR7 surface expression and internalization, and thus enhances CCR7-dependent migratory signaling activation. Consequently, Extl1 is required for DC-mediated Th1 and Th17 responses in immune defense against bacterial infection and for Treg cell development in the prevention of autoimmunity. Our study adds mechanistic insights to the regulation of CCR7-triggered DC migration in immunity and tolerance and provides a potential target for the treatment of infectious and autoimmune diseases.

Keywords: CCR7; CP: Immunology; Exostosin like glycosyltransferase 1; autoimmunity; bacterial infection; complement C1q; dendritic cell migration; heparan sulfate proteoglycans; immune defense; immune tolerance; inflammation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autoimmune Diseases* / metabolism
Autoimmunity
Cell Movement
Complement C1q / metabolism
Dendritic Cells* / metabolism
Heparan Sulfate Proteoglycans / metabolism
Humans
Receptors, CCR7 / metabolism

Substances

Receptors, CCR7
Complement C1q
Heparan Sulfate Proteoglycans
CCR7 protein, human