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Complement Receptor Cr1 Require Expression of the Mouse and T Optimal Germinal Center B Cell Activation and T-Dependent Antibody Responses Require Expression of the Mouse Complement Receptor Cr1 This information is current as of September 24, 2021. Luke R. Donius, Jennifer M. Handy, Janis J. Weis and John H. Weis J Immunol 2013; 191:434-447; Prepublished online 3 June 2013; doi: 10.4049/jimmunol.1203176 Downloaded from http://www.jimmunol.org/content/191/1/434 Supplementary http://www.jimmunol.org/content/suppl/2013/06/03/jimmunol.120317 http://www.jimmunol.org/ Material 6.DC1 References This article cites 46 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/191/1/434.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 24, 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 © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Optimal Germinal Center B Cell Activation and T-Dependent Antibody Responses Require Expression of the Mouse Complement Receptor Cr1 Luke R. Donius, Jennifer M. Handy, Janis J. Weis, and John H. Weis Follicular dendritic cells (FDCs) and complement receptor (Cr)1 and complement receptor (Cr)2 are important for the generation of humoral immunity. Cr1/2 expression on B cells and FDCs was shown to provide a secondary signal for B cell activation, to facilitate transport of Ag in immune follicles, and to enhance retention of immune complexes by FDCs. We show in this study that murine B cells predominantly express the Cr2 product from the Cr2 gene, whereas FDCs almost exclusively express the Cr1 isoform generated from the Cr2 gene. To define the specific role of Cr1, we created an animal that maintains normal cell-restricted expression of Cr2 but does not express Cr1. Cr1-deficient (Cr1KO) mice develop normal B1 and B2 immature and mature B cell Downloaded from subsets and have normal levels of naive serum Abs but altered levels of natural Abs. Immunization of the Cr1KO animal demonstrates deficient Ab responses to T-dependent, but not T-independent, Ags. Germinal centers from the immunized Cr1KO animal possess a deficiency in activated B cells, similar to that seen for animals lacking both Cr1 and Cr2 or C3. Finally, animals lacking only Cr1 respond similarly to wild-type animals to infections with Streptococcus pneumoniae, a pathogen to which animals lacking C3 or both Cr1 and Cr2 are particularly sensitive. Altogether, these data suggest that the production of Cr1, primarily by FDCs, is critical in the generation of appropriately activated B cells of the germinal center and the generation of mature Ab http://www.jimmunol.org/ responses. The Journal of Immunology, 2013, 191: 434–447. ntibodies (Igs) are the major effectors of the adaptive activated germinal center (GC) B cells must then retest their new Ig immune response, and different isotype classes of Ab are before undergoing clonal expansion and differentiation to either A produced to achieve different effects with Ab of the same a plasma or memory cell. FDCs play an integral role in retention specificity. Ig class-switch recombination is a hallmark of B cell of Ag for this test of the new Ig, as well. Transport to and capture of responses to T-dependent (TD) Ags (1). These reactions occur Ag by FDCs in a primary immune response uses the protein products within immune follicles of secondary immune structures, such as the of the mouse Cr2 gene: complement receptor (Cr)1 and complement spleen and lymph nodes (2). Central to follicles are follicular den- receptor (Cr)2 (4). by guest on September 24, 2021 dritic cells (FDCs), which establish the zonal identity (3) and act as The predominant role of the complement cascade is detection of a concentrated depot of Ag. In the course of an immune challenge, danger signals via the classical, mannose-binding lectin and alter- Ag is trafficked to the FDCs (4–6), where follicular B cells are native pathways and targeting of bound cells for lytic killing by the recruited for surveillance of retained Ag. BCR specificity for an Ag membrane attack complex (7–9). However, in addition to targeting retained on an FDC results in internalization and processing for foreign cells for membrane attack complex lysis, opsonization by the presentation to T cells. The B cell then migrates to the T cell zone and protein C3 can be used in transport to an FDC, phagocytosis, sec- presents the processed peptide to Th cells in the context of class II ondary signals through various complement receptors, and activation MHC. Upon a secondary signal from a peptide-specific Th cell, this of more complement. These outcomes are dependent on the cleavage B cell undergoes somatic hypermutation and isotype switch. These fragment of C3 and the corresponding cell receptor that they en- counter. C3 is central to all three complement pathways; upon acti- vation, it is cleaved into C3b and C3a. C3a is a potent anaphylatoxin Division of Cell Biology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112 that diffuses away to recruit and activate cells, whereas C3b remains bound to the foreign molecule and forms a C3 convertase complex that Received for publication November 19, 2012. Accepted for publication May 5, 2013. cleaves more C3. Alternatively, in the presence of the complement This work was supported by Public Health Service Grants AI-24158 and AI-088451 (to J.H.W.) and AI-32223 and AI-43521 (to J.J.W.), Training Program in Microbial regulator, factor I, and one of the cofactors—factor H, Crry, or Cr1— Pathogenesis 5T32-AI-055434 (to L.R.D.), and funds from the George J. Weber C3b can be cleaved into one of the enzymatically inactive fragments: Presidential Endowed Chair (to J.H.W.). iC3b or C3d(g). Activation of the complement pathway can modulate Address correspondence and reprint requests to Dr. John H. Weis, Division of Cell humoral immunity (10) through the complement receptors 1 and 2 Biology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112. E-mail address: [email protected] (Cr1 and Cr2) (11–14). Both Cr1 and Cr2 can bind the terminal The online version of this article contains supplemental material. cleavage products of C3: iC3b, and C3d(g). In addition, Cr1 is capable of binding the enzymatically active C3 convertase subunit C3b and Abbreviations used in this article: C3KO, complement component C3 knockout; Cr1, complement receptor 1; Cr2, complement receptor 2; Cr1KO, complement acting as a cofactor for factor I cleavage of C3b to iC3b or C3d(g) (15). receptor 1 knockout; Cr1/2KO, complement receptor 1 and 2 knockout; dpi, days The mouse differs from the human in that the single mouse Cr2 postinfection; DZ, dark zone; FDC, follicular dendritic cell; FOB, follicular mature B cell; GC, germinal center; KLH, keyhole limpet hemocyanin; LZ, light zone; MFI, gene encodes both Cr1 and Cr2 via alternative splicing, whereas mean fluorescent intensity; MZB, marginal zone B cell; PBT, 0.1% Tween-20 in 13 primates use distinct genes for the CR1 and CR2 proteins (16). PBS; T1, transition 1; T2, transition 2; TD, T dependent; TI, T independent; TNP, Expression of the mouse Cr2 gene by B cells and FDCs has long trinitrophenyl; WT, wild-type. been held under the assumption that the two different isoforms, Copyright Ó 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00 Cr1 and Cr2, are produced equally in both of these distinct cell www.jimmunol.org/cgi/doi/10.4049/jimmunol.1203176 The Journal of Immunology 435 types. Functionally, mouse knockout models addressed the loss of AC-39) that generated a 350-bp product. All experiments were carried out both Cr1 and Cr2 when critical sequences of the Cr2 gene were using Cr1KO mice backcrossed to C57BL/6 or BALB/C mice for at least five deleted (12, 13). These studies did not delineate the specific generations. WT C57BL/6 and BALB/C mice, as well as complement component 3–deficient (C3KO) mice, were purchased from The Jackson functions of the Cr1 and Cr2 proteins on B cells and FDCs, and Laboratory (Bar Harbor, ME) or obtained from colonies bred on location. elevated surface expression of CD19 on Cr1/2-deficient (Cr1/ C57BL/6-derived (Cr1KO, Cr1/2KO, C3KO, and WT) (12) 8–16-wk-old 2KO) B cells was proposed to lead to B cell anergy (17). Addi- male and female mice were used in all experiments, unless otherwise tional studies also used Cr1/2KO animals to examine the function specified. Mice were sex matched across genotypes. All mice were housed at the Comparative Medicine Center (University of Utah Health Sciences of human CR1 or CR2 via transgenic-expression models of these Center) in accordance with the National Institutes of Health guidelines for proteins using Ig gene promoters (18, 19). In these studies, how- the care and use of laboratory animals. Mice were housed in an Animal ever, premature expression of the transgenes (compared with na- Biosafety Level 2 protocol–approved area for all Streptococcus pneumo- tive Cr2), lack of FDC expression, expression in inappropriate niae infection experiments.
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