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(RP105) Activates B Cells to Rapidly Produce Polyclonal Ig Via a T Cell and Myd88-Independent Pathway

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(RP105) Activates B Cells to Rapidly Produce Polyclonal Ig Via a T Cell and Myd88-Independent Pathway Anti-CD180 (RP105) Activates B Cells To Rapidly Produce Polyclonal Ig via a T Cell and MyD88-Independent Pathway This information is current as Jay W. Chaplin, Shinji Kasahara, Edward A. Clark and of October 6, 2021. Jeffrey A. Ledbetter J Immunol 2011; 187:4199-4209; Prepublished online 14 September 2011; doi: 10.4049/jimmunol.1100198 http://www.jimmunol.org/content/187/8/4199 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2011/09/14/jimmunol.110019 Material 8.DC1 http://www.jimmunol.org/ References This article cites 33 articles, 16 of which you can access for free at: http://www.jimmunol.org/content/187/8/4199.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 6, 2021 • 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 © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Anti-CD180 (RP105) Activates B Cells To Rapidly Produce Polyclonal Ig via a T Cell and MyD88-Independent Pathway Jay W. Chaplin,*,†,‡ Shinji Kasahara,† Edward A. Clark,† and Jeffrey A. Ledbetter* CD180 is homologous to TLR4 and regulates TLR4 signaling, yet its function is unclear. We report that injection of anti-CD180 mAb into mice induced rapid Ig production of all classes and subclasses, with the exception of IgA and IgG2b, with up to 50-fold increases in serum IgG1 and IgG3. IgG production after anti-CD180 injection was not due to reactivation of memory B cells and was retained in T cell-deficient (TCR knockout [KO]), CD40 KO, IL-4 KO, and MyD88 KO mice. Anti-CD180 rapidly increased both transitional and mature B cells, with especially robust increases in transitional B cell number, marginal zone B cell pro- liferation, and CD86, but not CD80, expression. In contrast, anti-CD40 induced primarily follicular B cell and myeloid expansion, with increases in expression of CD80 and CD95 but not CD86. The expansion of splenic B cells was due, in part, to proliferation and occurred in wild-type and TCR KO mice, whereas T cell expansion occurred in wild-type, but not in B cell-deficient, mice, indicating a direct role for B cells in CD180 stimulation in vivo. Combination of anti-CD180 with various MyD88-dependent TLR Downloaded from ligands biased B cell fate because coinjection diminished Ig production, but purified B cells exhibited synergistic proliferation. Anti-CD180 had no effect on cytokine production from B cells, but it increased IL-6, IL-10, and TNF-a production in combination with LPS or CpG. Thus, CD180 stimulation induces intrinsic B cell proliferation and differentiation, causing rapid increases in IgG, and integrates MyD88-dependent TLR signals to regulate proliferation, cytokine production, and differentiation. The Journal of Immunology, 2011, 187: 4199–4209. http://www.jimmunol.org/ D180 (RP105) was originally identified as a B cell surface stream signaling (7, 8). Although each TLR exhibits specificity molecule mediating activation and proliferation; it was for agonists with conserved molecular structures, combinations C later recognized as a TLR homolog (1, 2). It is a leucine- of TLR signals mediate much more robust and specific responses rich repeat type 1 membrane protein with high extracellular ho- appropriate for fine-tuning against particular pathogens (9, 10). mology to the LPS receptor (2); however, unlike TLR4, its ex- Because CD180 is classified as a TLR, it is essential to understand pression is restricted to APCs (B cells, macrophages, and dendritic its interaction with other TLRs, because multiple TLRs are often cells [DCs]) (3). CD180 and TLR4 are also similar in that mAbs required in concert to mediate full physiological function. to these receptors cause B cell proliferation and upregulation In CD180 knockout (KO) mice, B cell responses to LPS are by guest on October 6, 2021 of costimulatory molecules (CD86) (4). However, although TLR4 impaired, and constitutive serum IgG3 is reduced (11). These data agonists induce only a subset of B cells to proliferate (15%) (5), supported a model of CD180 as a required coreceptor for B cell anti-CD180 activates .85% of both human and mouse B cells responses to bacterial cell wall components (12), binding LPS and in vitro, causing extensive proliferation. forming heterodimers with TLR4 to enhance signaling. However, TLRs recognize conserved microbial components to initiate although the natural ligand of CD180 is unknown, it is not LPS. rapid responses that both prime and skew adaptive immunity (6). CD180 does not bind LPS (3), and structural analysis of the Each TLR binds specific ligands via its extracellular domain to CD180 complex revealed that it does not contain the required initiate dimerization, recruitment of MyD88 and/or TRIF intra- LPS-binding pocket (13), because only four, not six, acyl chains cellular adaptors to the Toll/IL-1R (TIR) domain, and down- can fit (14). Therefore, although CD180 regulates B cell sensi- tivity to LPS, the mechanism of CD180 support for TLR4 signals remains unknown. Because CD180 lacks the cytoplasmic TIR *Division of Rheumatology, Department of Medicine; University of Washington, Seattle, WA 98195; †Department of Immunology, University of Washington, Seattle, domain common to all other TLRs, seeming instead to initiate an WA 98195; and ‡Molecular and Cellular Biology Program, University of Washing- AgR-like phosphotyrosine and calcium-based signaling cascade in ton, Seattle, WA 98195 B cells (1, 15–17), there is no known point of interaction between Received for publication February 4, 2011. Accepted for publication August 16, the CD180 and TLR pathways. Furthermore, it is unclear how 2011. a scaffold of dimerized (18, 19) TIR domains forms with inclusion This work was supported by National Institutes of Health Grants AI52203 (to E.A.C.), of CD180 in a heterodimer with TLR4. This led to an opposing AI44257 (to E.A.C.), and AI85311 (to J.A.L.); Washington State Life Science Dis- covery Fund 2087750 (to E.A.C. and J.A.L.); the Townsend-Henderson Endowment model in which CD180 forms inactive heterodimers with TLR4 (to J.W.C.); and Public Health Service, National Research Service Award 2T32 and specifically attenuates LPS responses in myeloid cells, with GM007270 from the National Institute of General Medical Sciences (to J.W.C.). only artifactual stimulation of B cells (3). Address correspondence and reprint requests to Jay W. Chaplin, Department of Current literature is confusing because it ascribes opposing Immunology, University of Washington, Box 357650, 1959 NE Pacific Street, Seat- tle, WA 98195. E-mail address: [email protected]. functions to CD180, both as a required coreceptor for LPS/ The online version of this article contains supplemental material. stimulator of B cells (11) and as a specific TLR4 inhibitor in Abbreviations used in this article: CGG, chicken g-globulin; CI, combination index; DCs with no physiological effect on B cells (20). Although DC, dendritic cell; FO, follicular; KO, knockout; mMT, B cell deficient; MZ, mar- CD180 deficiency has been characterized (3, 11), neither CD180 ginal zone; NP, 4-hydroxy-3-nitro-phenacetyl; T1, transitional 1; T2, transitional 2; stimulation in vivo nor the integration of CD180 and TLR signals TI, T cell independent; TIR, Toll/IL-1R; WT, wild-type. has been studied, with the single exception of noting increases in + Copyright Ó 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 CD138 B cells in spleen sections following anti-CD180 injection www.jimmunol.org/cgi/doi/10.4049/jimmunol.1100198 4200 ANTI-CD180 ACTIVATES B CELLS TO PRODUCE POLYCLONAL Ig (11). In this article, we report that anti-CD180 mAb in vivo Analysis of lymphocyte subsets and proliferation induces rapid polyclonal B cell expansion and striking Ig pro- Flow cytometry analyses were performed on either a standard FACScan or duction, especially of the IgG1 and IgG3 subclasses. This Ig pro- FACSCanto (Becton Dickinson, Franklin Lakes, NJ). Minimums of 30,000 duction is inhibited by coadministration of diverse TLR ligands. cells of the final gated population were used for all analyses. Data analysis In contrast, anti-CD180 synergizes with ligands for all MyD88- was performed with FlowJo software (Tree Star, Ashland, OR). Staining dependent TLRs to increase B cell proliferation. Although anti- was performed for CD3, CD24, CD80, and CD95 (Becton Dickinson clones 145-2c11, M1/69, 16-10A1, and Jo2); CD4, CD8b, CD19, CD21, CD23, CD180, in combination with TLR, signals augmented cytokine CD25, and CD69 (BioLegend clones RM4-5, YTS156.7.7, 6D5, 7E9, production from purified B cells, it does not, by itself, induce B3B4, 3C7, and H1.2F3); and CD5, CD45R/B220, and CD86 (clones 53- cytokine production. Our data indicated that CD180 signals act 7.3, RA3-6B2, and GL1; eBioscience, San Diego, CA). Mouse anti-rat IgG directly on B cells to induce strong polyclonal B cell proliferation secondary Ab was from Jackson ImmunoResearch. BrdU analysis was performed according to the kit’s instructions (Becton Dickinson), follow- and Ig production and that integration of TLR and CD180 signals ing a 1-h pulse delivered by i.p. injection on day 3 after anti-CD180 in- through MyD88 skews B cells toward proliferation and cytokine jection.
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