Kindlin-3 maintains marginal zone B cells but confines follicular B cell activation and differentiation.
B cell activation
CXCR5
Integrin adhesion
follicular B cells
marginal zone B cells
Journal
Journal of leukocyte biology
ISSN: 1938-3673
Titre abrégé: J Leukoc Biol
Pays: England
ID NLM: 8405628
Informations de publication
Date de publication:
04 2022
04 2022
Historique:
pubmed:
11
12
2021
medline:
11
5
2022
entrez:
10
12
2021
Statut:
ppublish
Résumé
Integrin-mediated interactions between hematopoietic cells and their microenvironment are important for the development and function of immune cells. Here, the role of the integrin adaptor Kindlin-3 in B cell homeostasis is studied. Comparing the individual steps of B cell development in B cell-specific Kindlin-3 or alpha4 integrin knockout mice, we found in both conditions a phenotype of reduced late immature, mature, and recirculating B cells in the bone marrow. In the spleen, constitutive B cell-specific Kindlin-3 knockout caused a loss of marginal zone B cells and an unexpected expansion of follicular B cells. Alpha4 integrin deficiency did not induce this phenotype. In Kindlin-3 knockout B cells VLA-4 as well as LFA-1-mediated adhesion was abrogated, and short-term homing of these cells in vivo was redirected to the spleen. Upon inducible Kindlin-3 knockout, marginal zone B cells were lost due to defective retention within 2 weeks, while follicular B cell numbers were unaltered. Kindlin-3 deficient follicular B cells displayed higher IgD, CD40, CD44, CXCR5, and EBI2 levels, and elevated PI3K signaling upon CXCR5 stimulation. They also showed transcriptional signatures of spontaneous follicular B cell activation. This activation manifested in scattered germinal centers in situ, early plasmablasts differentiation, and signs of IgG class switch.
Identifiants
pubmed: 34888947
doi: 10.1002/JLB.1HI0621-313R
doi:
Substances chimiques
Cytoskeletal Proteins
0
Lymphocyte Function-Associated Antigen-1
0
kindlin-3 protein, mouse
0
Integrin alpha4
143198-26-9
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
745-758Informations de copyright
© 2021 The Authors. Journal of Leukocyte Biology published by Wiley Periodicals LLC on behalf of Society for Leukocyte Biology.
Références
Abram CL, Lowell CA. The ins and outs of leukocyte integrin signaling. Annu Rev Immunol. 2009;27:339-62.
Arroyo AG, Yang JT, Rayburn H, Hynes RO. Differential requirements for alpha4 integrins during fetal and adult hematopoiesis. Cell. 1996;85:997-1008.
Papayannopoulou T, Craddock C, Nakamoto B, Priestley GV, Wolf NS. The VLA4/VCAM-1 adhesion pathway defines contrasting mechanisms of lodgement of transplanted murine hemopoietic progenitors between bone marrow and spleen. Proc Natl Acad Sci U S A. 1995;92:9647-51.
Oostendorp RA, Dormer P. VLA-4-mediated interactions between normal human hematopoietic progenitors and stromal cells. Leuk Lymphoma. 1997;24:423-35.
Carrasco YR, Batista FD. B-cell activation by membrane-bound antigens is facilitated by the interaction of VLA-4 with VCAM-1. EMBO J. 2006;25:889-99.
Carrasco YR, Fleire SJ, Cameron T, Dustin ML, Batista FD. LFA-1/ICAM-1 interaction lowers the threshold of B cell activation by facilitating B cell adhesion and synapse formation. Immunity. 2004;20:589-99.
Gutjahr JC, Bayer E, Yu X, et al. CD44 engagement enhances acute myeloid leukemia cell adhesion to the bone marrow microenvironment by increasing VLA-4 avidity. Haematologica. 2021;106:2102-2113.
Harzschel A, Zucchetto A, Gattei V, Hartmann TN. VLA-4 Expression and Activation in B Cell Malignancies: functional and Clinical Aspects. Int J Mol Sci. 2020;21.
Tissino E, Benedetti D, Herman SEM, et al. Functional and clinical relevance of VLA-4 (CD49d/CD29) in ibrutinib-treated chronic lymphocytic leukemia. J Exp Med. 2018;215:681-697.
Calderwood DA, Campbell ID, Critchley DR. Talins and kindlins: partners in integrin-mediated adhesion. Nat Rev Mol Cell Biol. 2013;14:503-17.
Moser M, Legate KR, Zent R, Fassler R. The tail of integrins, talin, and kindlins. Science. 2009;324:895-9.
Ussar S, Wang HV, Linder S, Fassler R, Moser M. The Kindlins: subcellular localization and expression during murine development. Exp Cell Res. 2006;312:3142-51.
Ruppert R, Moser M, Sperandio M, et al. Kindlin-3-mediated integrin adhesion is dispensable for quiescent but essential for activated hematopoietic stem cells. J Exp Med. 2015;212:1415-32.
Moretti FA, Moser M, Lyck R, et al. Kindlin-3 regulates integrin activation and adhesion reinforcement of effector T cells. Proc Natl Acad Sci U S A. 2013;110:17005-10.
Moser M, Bauer M, Schmid S, et al. Kindlin-3 is required for beta2 integrin-mediated leukocyte adhesion to endothelial cells. Nat Med. 2009;15:300-5.
Moser M, Nieswandt B, Ussar S, Pozgajova M, Fassler R. Kindlin-3 is essential for integrin activation and platelet aggregation. Nat Med. 2008;14:325-30.
Hartmann TN, Grabovsky V, Wang W, et al. Circulating B-cell chronic lymphocytic leukemia cells display impaired migration to lymph nodes and bone marrow. Cancer Res. 2009;69:3121-30.
Hobeika E, Thiemann S, Storch B, et al. Testing gene function early in the B cell lineage in mb1-cre mice. Proc Natl Acad Sci U S A. 2006;103:13789-94.
Cohen SJ, Gurevich I, Feigelson SW, et al. The integrin coactivator Kindlin-3 is not required for lymphocyte diapedesis. Blood. 2013;122:2609-17.
Scott L M, Priestley G V, Papayannopoulou T, (2003) Deletion of alpha4 integrins from adult hematopoietic cells reveals roles in homeostasis, regeneration, and homing. Mol Cell Biol 23, 9349-60.
Brachtl, G, Sahakyan, K, Denk, U et al. (2011) Differential bone marrow homing capacity of VLA-4 and CD38 high expressing chronic lymphocytic leukemia cells. PLoS One 6, e23758.
Ganghammer, S, Hutterer, E, Hinterseer, E et al. (2015) CXCL12-induced VLA-4 activation is impaired in trisomy 12 chronic lymphocytic leukemia cells: a role for CCL21. Oncotarget 6, 12048-60.
Chigaev, A, Blenc, AM, Braaten, JV et al. (2001) Real time analysis of the affinity regulation of alpha 4-integrin. The physiologically activated receptor is intermediate in affinity between resting and Mn(2+) or antibody activation. J Biol Chem 276, 48670-8.
Tummino, PJ and Copeland, RA (2008) Residence time of receptor-ligand complexes and its effect on biological function. Biochemistry 47, 5481-92.
Carvalho, BS and Irizarry, RA (2010) A framework for oligonucleotide microarray preprocessing. Bioinformatics 26, 2363-7.
Ritchie, ME, Phipson, B, Wu, D et al. (2015) limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43, e47.
Liberzon, A, Birger, C, Thorvaldsdottir, H, Ghandi, M, Mesirov, JP, Tamayo, P (2015) The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst 1, 417-425.
Korotkevich, G, Sukhov, V, Budin, N, Shpak, B, Artyomov, MN, Sergushichev, A (2021) Fast gene set enrichment analysis. 060012.
Beck, TC, Gomes, AC, Cyster, JG, Pereira, JP (2014) CXCR4 and a cell-extrinsic mechanism control immature B lymphocyte egress from bone marrow. J Exp Med 211, 2567-81.
Lokmic, Z, Lammermann, T, Sixt, M, Cardell, S, Hallmann, R, Sorokin, L (2008) The extracellular matrix of the spleen as a potential organizer of immune cell compartments. Semin Immunol 20, 4-13.
Muzumdar, MD, Tasic, B, Miyamichi, K, Li, L, Luo, L (2007) A global double-fluorescent Cre reporter mouse. Genesis 45, 593-605.
Schulz, O, Hammerschmidt, SI, Moschovakis, GL, Forster, R (2016) Chemokines and Chemokine Receptors in Lymphoid Tissue Dynamics. Annu Rev Immunol 34, 203-42.
Gutjahr, JC, Szenes, E, Tschech, L et al. (2018) Microenvironment-induced CD44v6 promotes early disease progression in chronic lymphocytic leukemia. Blood 131, 1337-1349.
Protin, U, Schweighoffer, T, Jochum, W, Hilberg, F (1999) CD44-deficient mice develop normally with changes in subpopulations and recirculation of lymphocyte subsets. J Immunol 163, 4917-23.
Hartmann, TN, Grabovsky, V, Pasvolsky, R et al. (2008) A crosstalk between intracellular CXCR7 and CXCR4 involved in rapid CXCL12-triggered integrin activation but not in chemokine-triggered motility of human T lymphocytes and CD34+ cells. J Leukoc Biol 84, 1130-40.
Allen, CD, Ansel, KM, Low, C et al. (2004) Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nat Immunol 5, 943-52.
Gatto, D, Paus, D, Basten, A, Mackay, CR, Brink, R (2009) Guidance of B cells by the orphan G protein-coupled receptor EBI2 shapes humoral immune responses. Immunity 31, 259-69.
Pereira, JP, Kelly, LM, Xu, Y, Cyster, JG (2009) EBI2 mediates B cell segregation between the outer and centre follicle. Nature 460, 1122-6.
Wu, BX, Zhao, LD, Zhang, X (2019) CXCR4 and CXCR5 orchestrate dynamic germinal center reactions and may contribute to the pathogenesis of systemic lupus erythematosus. Cell Mol Immunol 16, 724-726.
Cinamon, G, Zachariah, MA, Lam, OM, Foss, FW Jr, Cyster, JG (2008) Follicular shuttling of marginal zone B cells facilitates antigen transport. Nat Immunol 9, 54-62.
Manevich-Mendelson, E, Grabovsky, V, Feigelson, SW et al. (2010) Talin1 is required for integrin-dependent B lymphocyte homing to lymph nodes and the bone marrow but not for follicular B-cell maturation in the spleen. Blood 116, 5907-18.
Lu, TT and Cyster, JG (2002) Integrin-mediated long-term B cell retention in the splenic marginal zone. Science 297, 409-12.
Guinamard, R, Okigaki, M, Schlessinger, J, Ravetch, JV (2000) Absence of marginal zone B cells in Pyk-2-deficient mice defines their role in the humoral response. Nat Immunol 1, 31-6.
Tedford, K, Steiner, M, Koshutin, S et al. (2017) The opposing forces of shear flow and sphingosine-1-phosphate control marginal zone B cell shuttling. Nat Commun 8, 2261.
Pereira, JP, An, J, Xu, Y, Huang, Y, Cyster, JG (2009) Cannabinoid receptor 2 mediates the retention of immature B cells in bone marrow sinusoids. Nat Immunol 10, 403-11.
Hyduk, SJ, Rullo, J, Cano, AP et al. (2011) Talin-1 and kindlin-3 regulate alpha4beta1 integrin-mediated adhesion stabilization, but not G protein-coupled receptor-induced affinity upregulation. J Immunol 187, 4360-8.
Manevich-Mendelson, E, Feigelson, SW, Pasvolsky, R et al. (2009) Loss of Kindlin-3 in LAD-III eliminates LFA-1 but not VLA-4 adhesiveness developed under shear flow conditions. Blood 114, 2344-53.
Klapproth, S, Moretti, FA, Zeiler, M et al. (2015) Minimal amounts of kindlin-3 suffice for basal platelet and leukocyte functions in mice. Blood 126, 2592-600.
Kuokkanen, E, Sustar, V, Mattila, PK (2015) Molecular control of B cell activation and immunological synapse formation. Traffic 16, 311-26.
Dong, JM, Lau, LS, Ng, YW, Lim, L, Manser, E (2009) Paxillin nuclear-cytoplasmic localization is regulated by phosphorylation of the LD4 motif: evidence that nuclear paxillin promotes cell proliferation. Biochem J 418, 173-84.
Lim, ST, Miller, NL, Chen, XL et al. (2012) Nuclear-localized focal adhesion kinase regulates inflammatory VCAM-1 expression. J Cell Biol 197, 907-19.
Qu, J, Ero, R, Feng, C et al. (2015) Kindlin-3 interacts with the ribosome and regulates c-Myc expression required for proliferation of chronic myeloid leukemia cells. Sci Rep 5, 18491.
Loder, F, Mutschler, B, Ray, RJ et al. (1999) B cell development in the spleen takes place in discrete steps and is determined by the quality of B cell receptor-derived signals. J Exp Med 190, 75-89.
Waters, LR, Ahsan, FM, Wolf, DM, Shirihai, O, Teitell, MA (2018) Initial B Cell Activation Induces Metabolic Reprogramming and Mitochondrial Remodeling. iScience 5, 99-109.
Lu, E and Cyster, JG (2019) G-protein coupled receptors and ligands that organize humoral immune responses. Immunol Rev 289, 158-172.
Saez de Guinoa, J, Barrio, L, Mellado, M, Carrasco, YR (2011) CXCL13/CXCR5 signaling enhances BCR-triggered B-cell activation by shaping cell dynamics. Blood 118, 1560-9.