title: Distinct chemokine signaling regulates integrin ligand specificity to dictate tissue-specific lymphocyte homing.
abstract: Immune surveillance and host defense depend on the precisely regulated trafficking of lymphocytes. Integrin α4β7 mediates lymphocyte homing to the gut through its interaction with mucosal vascular address in cell adhesion molecule-1 (MAdCAM-1). α4β7 also binds vascular cell adhesion molecule-1 (VCAM-1), which is expressed in other tissues. To maintain the tissue specificity of lymphocyte homing, α4β7 must distinguish one ligand from the other. Here, we demonstrate that α4β7 is activated by different chemokines in a ligand-specific manner. CCL25 stimulation promotes α4β7-mediated lymphocyte adhesion to MAdCAM-1 but suppresses adhesion to VCAM-1, whereas CXCL10 stimulation has the opposite effect. Using separate pathways, CCL25 and CXCL10 stimulate differential phosphorylation states of the β7 tail and distinct talin and kindlin-3 binding patterns, resulting in different binding affinities of MAdCAM-1 and VCAM-1 to α4β7. Thus, our findings provide a mechanism for lymphocyte traffic control through the unique ligand-specific regulation of integrin adhesion by different chemokines.
authors: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors: Hao
authors: H
authors: Sun
authors: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors: Jie
authors: J
authors: Liu
authors: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors: YaJuan
authors: Y
authors: Zheng
authors: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors: YouDong
authors: Y
authors: Pan
authors: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors: Kun
authors: K
authors: Zhang
authors: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: jfchen@sibcb.ac.cn.
authors: JianFeng
authors: J
authors: Chen
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002465:Cell Movement; D054357:Chemokine CXCL10 / Q000378:metabolism*; D054371:Chemokine CXCL11 / Q000378:metabolism*; D019742:Chemokines, CC / Q000378:metabolism; D005434:Flow Cytometry; D015151:Immunoblotting; D016023:Integrins / Q000502:physiology*; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009088:Mucoproteins; D009928:Organ Specificity; D010766:Phosphorylation; D011485:Protein Binding; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
chemical_list: C491541:Ccl25 protein, mouse; D015815:Cell Adhesion Molecules; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D019742:Chemokines, CC; D016023:Integrins; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; D019010:Vascular Cell Adhesion Molecule-1; C071777:integrin alpha4beta7