CXCL12 Regulates through JAK1 and JAK2 Formation of Productive Immunological Synapses.
The adaptive immune response requires interaction between T cells and APC to form a specialized structure termed the immune synapse (IS). Although the TCR is essential for IS organization, other factors such as chemokines participate in this process. In this study, we show that the chemokine CXCL12-mediated signaling contributes to correct IS organization and therefore influences T cell activation. CXCR4 downregulation or blockade on T cells caused defective actin polymerization at the contact site with APC, altered microtubule-organizing center polarization and the IS structure, and reduced T cell/APC contact duration. T cell activation was thus inhibited, as shown by reduced expression of CD25 and CD69 markers and of IL-2 mRNA levels. The results indicate that, through Gi and JAK1 and 2 kinases activation, CXCL12 signaling cooperates to build the IS and to maintain adhesive contacts between APC and T cells, required for continuous TCR signaling.
Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, E-28049 Madrid, Spain;
Graciela
G
Cascio
Servicio de Inmunología, Instituto de Investigación Sanitaria Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, E-28006 Madrid, Spain;
Noa B
NB
Martín-Cófreces
Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, E-28049 Madrid, Spain;
José Miguel
JM
Rodríguez-Frade
Departamento de Biología Vascular e Inflamación, Fundación Centro Nacional de Investigaciones Cardiovasculares-Carlos III, E-28029 Madrid, Spain; Centro de Investigaciones Biológicas/Consejo Superior de Investigaciones Cientificas, E-28040 Madrid, Spain; and.
Pilar
P
López-Cotarelo
Grupo de Enfermedades Inflamatorias y Autoinmunes, Instituto de Investigación Sanitaria Hospital 12 de Octubre, E-28041 Madrid, Spain.
Gabriel
G
Criado
Grupo de Enfermedades Inflamatorias y Autoinmunes, Instituto de Investigación Sanitaria Hospital 12 de Octubre, E-28041 Madrid, Spain.
José L
JL
Pablos
Departamento de Biología Vascular e Inflamación, Fundación Centro Nacional de Investigaciones Cardiovasculares-Carlos III, E-28029 Madrid, Spain; Centro de Investigaciones Biológicas/Consejo Superior de Investigaciones Cientificas, E-28040 Madrid, Spain; and.
José Luis
JL
Rodríguez-Fernández
Servicio de Inmunología, Instituto de Investigación Sanitaria Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, E-28006 Madrid, Spain;
Francisco
F
Sánchez-Madrid
Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas, E-28049 Madrid, Spain; mmellado@cnb.csic.es.
Mario
M
Mellado
D000199:Actins / Q000378:metabolism; D056704:Adaptive Immunity / Q000276:immunology; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000276:immunology*; D015536:Down-Regulation; D005260:Female; D054992:Immunological Synapses / Q000276:immunology*; D007376:Interleukin-2 / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D053613:Janus Kinase 1 / Q000276:immunology*; D053614:Janus Kinase 2 / Q000276:immunology*; D037181:Lectins, C-Type / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015398:Signal Transduction / Q000276:immunology; D000099192:CD69 Antigens
D000199:Actins; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D054377:Chemokine CXCL12; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D037181:Lectins, C-Type; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D019718:Receptors, CXCR4; D000099192:CD69 Antigens; C514936:CXCR4 protein, mouse; C515256:Cxcl12 protein, mouse; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse