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Associated Antigen-1 and Kindlin-3 This Information Is Current As of September 27, 2021 Optimal T Cell Activation and B Cell Antibody Responses In Vivo Require the Interaction between Leukocyte Function− Associated Antigen-1 and Kindlin-3 This information is current as of September 27, 2021. Vicky Louise Morrison, Liisa M. Uotila, Marc Llort Asens, Terhi Savinko and Susanna Carola Fagerholm J Immunol 2015; 195:105-115; Prepublished online 18 May 2015; doi: 10.4049/jimmunol.1402741 Downloaded from http://www.jimmunol.org/content/195/1/105 Supplementary http://www.jimmunol.org/content/suppl/2015/05/16/jimmunol.140274 http://www.jimmunol.org/ Material 1.DCSupplemental References This article cites 46 articles, 32 of which you can access for free at: http://www.jimmunol.org/content/195/1/105.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 27, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Optimal T Cell Activation and B Cell Antibody Responses In Vivo Require the Interaction between Leukocyte Function–Associated Antigen-1 and Kindlin-3 Vicky Louise Morrison,*,1 Liisa M. Uotila,*,1 Marc Llort Asens,* Terhi Savinko,* and Susanna Carola Fagerholm*,†,‡ 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 Tor B cell activation in vivo is unclear. In this study, we used TTT/AAA b2-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 Downloaded from 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 b2-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 http://www.jimmunol.org/ defects in neutrophil function, may be due, in part, to defects in lymphocyte trafficking and activation. The Journal of Immunology, 2015, 195: 105–115. ntegrins are heterodimeric cell surface adhesion molecules and subsequent IS formation between CD4 T cells and B cells consisting of a and b subunits. Expression of the b2 (CD18) allows the provision of help for B cell Ab production. Specifi- I integrin subfamily is restricted to leukocytes, where they cally, LFA-1 forms part of the peripheral supramolecular activation play important roles in cellular adhesion and migration in the cluster that surrounds the TCR or BCR cluster in the center, thus immune system (1). The b2-integrin family member leukocyte stabilizing the synapse and ensuring efficient lymphocyte activa- by guest on September 27, 2021 function–associated Ag-1 (LFA-1; aLb2, CD11a/CD18) is highly tion (7). It is thought that LFA-1 downstream signaling may also expressed in lymphocytes, namely B and T cells, and mediates contribute to the cellular activation signals, thus performing a co- binding to ICAMs on the surface of other cells. LFA-1 mediates stimulatory function, as was shown in T cells (8–10). However, firm adhesion to endothelial cells, which is necessary for extrav- the involvement of LFA-1 in T and B cell activation in vivo asation of lymphocytes from the bloodstream into lymph nodes remains controversial because of the difficulty in segregating the and sites of inflammation (2). Indeed, LFA-1–knockout mice roles of LFA-1 in migration versus activation. display impaired lymphocyte homing to these sites (3–6). Conformational changes in LFA-1 required for optimal ligand In addition to its role in cellular migration, LFA-1 is a key binding, as well as downstream integrin signaling, are regulated by component of the immunological synapse (IS) that forms between the binding of cytoplasmic factors to the integrin subunit intra- immune cells. For example, IS formation between APCs, such as cellular domains. Previously, we generated a mutant mouse line in dendritic cells (DCs), and CD4 T cells initiates T cell activation, which the threonine triplet in the b2-integrin tail was substituted with alanine residues (TTT/AAA b2-integrin knock-in (KI) mouse). This mutation abolishes binding of the important integrin regulator *Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland; kindlin-3 to the integrin cytoplasmic domain (11), resulting in im- †Medical Research Institute, University of Dundee, Dundee DD1 9SY, United King- dom; and ‡Faculty of Biological and Environmental Sciences, University of Helsinki, paired integrin activation to its high-affinity state and, therefore, 00014 Helsinki, Finland reduced integrin function. We showed that polyclonal activation of 1 V.L.M. and L.M.U. contributed equally to this work. TTT/AAA b2-integrin KI T cells in vitro with soluble anti-CD3 Received for publication October 29, 2014. Accepted for publication April 21, 2015. results in a reduction in T cell activation and proliferation com- This work was supported by the Academy of Finland, The Ella and Georg Ehrnrooth pared with wild-type (WT) T cells, whereas activation in response Foundation, The Sigrid Juselius Foundation, Biocentrum Helsinki, the Biotechnology to plate-bound anti-CD3 is unaffected by the KI mutation (11). and Biological Sciences Research Council, the Liv och Ha¨lsa Foundation, the Magnus Ehrnrooth Foundation, and Tenovus Scotland. Ag-specific T and B cell activation in vivo in these mice remains largely unexplored. Address correspondence and reprint requests to Dr. Susanna C. Fagerholm, Institute of Biotechnology, P.O. Box 56, 00014 University of Helsinki, Helsinki, Finland. Using integrin TTT/AAA b2-integrin KI and KI TCR-transgenic E-mail address: susanna.fagerholm@helsinki.fi (OT-II) mouse models, we show that Ag-specific CD4 T cell acti- The online version of this article contains supplemental material. vation in both an in vitro coculture system with DCs and in vivo in Abbreviations used in this article: BMDC, bone marrow–derived dendritic cell; DC, the spleen is dependent on the b2-integrin TTT site. We also reveal dendritic cell; Fo, follicular; IS, immunological synapse; KI, knock-in; LFA-1, leu- that optimal B cell numbers in lymph nodes and B cell Ab responses kocyte function–associated Ag-1; MZ, marginal zone; WT, wild-type. in vivo are dependent on fully functioning LFA-1 in leukocytes. Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 These results indicate a vital role for LFA-1–mediated firm adhesion www.jimmunol.org/cgi/doi/10.4049/jimmunol.1402741 106 INTEGRINS IN LYMPHOCYTE ACTIVATION in lymphocyte activation, even in circumstances where LFA-1– block (4.4G2) was included in all stains. Data were acquired on a LSR II mediated migration is unlikely to be involved. flow cytometer (Becton Dickinson) and analyzed using FlowJo software (TreeStar). Materials and Methods Real-time quantitative PCR Mice Spleen tissue of WTand KI mice was homogenized with ULTRA-TURRAX Mice were bred and maintained at the University of Dundee or the Uni- T8 (IKA) in RA1 included in the NucleoSpin RNA II Total RNA isolation versity of Helsinki, in compliance with national and local rules. The TTT/ kit (MACHEREY-NAGEL; Bioline, London, U.K.). RNA was extracted according to the manufacturer’s instructions and used as a template for AAA b2-integrin KI mouse line was described previously (11). The KI mice were crossed with OT-II mice (provided by Prof. Colin Watts, Uni- cDNA synthesis. cDNA was synthesized from 0.5 mg total RNA with versity of Dundee) to generate homozygote Itgb2 KI mice expressing the a High Capacity cDNA Reverse Transcription Kit (Applied Biosystems, Life Technologies). PCR primers and probes were obtained from Life OT-II transgene. Expression of the v-a2 and v-b5 TCR subunits was confirmed by flow cytometry, and the KI mutation as confirmed by PCR. Technologies. A TaqMan gene expression assay was performed with C57BL/6 mice were purchased from Charles River. In all experiments, TaqMan Fast Advanced MasterMix, and quantitative real-time PCR was age- and sex-matched mice were used. performed with a 7500 Fast Real-Time PCR System and SDS Software v.1.4.0 (Applied Biosystems). Gene expression was normalized with 18S Cell preparation rRNA, and target gene expression was calculated by the comparative CT method (Applied Biosystems). Bone marrow–derived dendritic cells (BMDCs) were generated by cul- turing mouse bone marrow for 10 d in 10 ng/ml GM-CSF (PeproTech) in ELISAs nontissue culture–treated petri dishes.
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