title: Optimal T Cell Activation and B Cell Antibody Responses In Vivo Require the Interaction between Leukocyte Function-Associated Antigen-1 and Kindlin-3.
abstract: Kindlin-3 is an important integrin regulator that is mutated in the rare genetic disorder, leukocyte adhesion deficiency type III, a disorder characterized by defective neutrophil trafficking and platelet function, leading to recurrent bacterial infections and bleeding. Kindlin-3 is also known to regulate T cell adhesion in vitro and trafficking in vivo, but whether the integrin/kindlin interaction regulates T or B cell activation in vivo is unclear. In this study, we used TTT/AAA β2-integrin knock-in (KI) mice and TCR-transgenic (OT-II) KI mice, in which the integrin/kindlin connection is disrupted, to investigate the role of the integrin/kindlin interaction in T cell activation. We show that basal T cell activation status in these animals in vivo is normal, but they display reduced T cell activation by wild-type Ag-loaded dendritic cells in vitro. In addition, T cell activation in vivo is reduced. We also show that basal Ab levels are normal in TTT/AAA β2-integrin KI mice, but B cell numbers in lymph nodes and IgG and IgM production after immunization are reduced. In conclusion, we show that the integrin/kindlin interaction is required for trafficking of immune cells, as well as for T cell activation and B cell Ab responses in vivo. These results imply that the immunodeficiency found in leukocyte adhesion deficiency type III patients, in addition to being caused by defects in neutrophil function, may be due, in part, to defects in lymphocyte trafficking and activation.
authors.affiliation: Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland;
authors.forename: Vicky Louise
authors.initials: VL
authors.lastname: Morrison
authors.affiliation: Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland;
authors.forename: Liisa M
authors.initials: LM
authors.lastname: Uotila
authors.affiliation: Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland;
authors.forename: Marc
authors.initials: M
authors.lastname: Llort Asens
authors.affiliation: Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland;
authors.forename: Terhi
authors.initials: T
authors.lastname: Savinko
authors.affiliation: Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland; Medical Research Institute, University of Dundee, Dundee DD1 9SY, United Kingdom; and Faculty of Biological and Environmental Sciences, University of Helsinki, 00014 Helsinki, Finland susanna.fagerholm@helsinki.fi.
authors.forename: Susanna Carola
authors.initials: SC
authors.lastname: Fagerholm
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018821:CD18 Antigens / Q000235:genetics / Q000276:immunology*; D002465:Cell Movement; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
chemical_list: D018821:CD18 Antigens; D003598:Cytoskeletal Proteins; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D016169:Lymphocyte Function-Associated Antigen-1; D011948:Receptors, Antigen, T-Cell; C527818:kindlin-3 protein, mouse