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Igm Cellular Dynamics of Memory B Cell Cellular Dynamics of Memory B Cell Populations: IgM + and IgG+ Memory B Cells Persist Indefinitely as Quiescent Cells This information is current as Derek D. Jones, Joel R. Wilmore and David Allman of September 24, 2021. J Immunol published online 5 October 2015 http://www.jimmunol.org/content/early/2015/10/03/jimmun ol.1501365 Downloaded from Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision http://www.jimmunol.org/ • 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 by guest on September 24, 2021 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. Published October 5, 2015, doi:10.4049/jimmunol.1501365 The Journal of Immunology Cellular Dynamics of Memory B Cell Populations: IgM+ and IgG+ Memory B Cells Persist Indefinitely as Quiescent Cells Derek D. Jones, Joel R. Wilmore, and David Allman Despite their critical role in long-term immunity, the life span of individual memory B cells remains poorly defined. Using a tet- racycline-regulated pulse-chase system, we measured population turnover rates and individual t1/2 of pre-established Ag-induced Ig class-switched and IgM-positive memory B cells over 402 d. Our results indicate that, once established, both IgG-positive and less frequent IgM-positive memory populations are exceptionally stable, with little evidence of attrition or cellular turnover. Indeed, the vast majority of cells in both pools exhibited t1/2 that appear to exceed the life span of the mouse, contrasting dramatically with mature naive B cells. These results indicate that recall Ab responses are mediated by stable pools of extremely long-lived cells, and suggest that Ag-experienced B cells employ remarkably efficient survival mechanisms. The Journal of Immunology, 2015, 195: 000–000. Downloaded from emory B cells mediate robust recall responses by vated cells, there is little information on the steady-state dynamics differentiating rapidly into Ab-secreting plasma cells of established memory B cell populations. M and forming nascent germinal centers (GCs), and by Several groups have since sought to define the life span of serving as effective APCs (1–4). Because secondary Ab responses memory B cells; however, the results have not led to a clear can be induced long after initial Ag encounter (5), it is generally consensus. Using a BCR transgenic system, Anderson et al. (11) http://www.jimmunol.org/ assumed that individual memory B cells are exceptionally long- showed that memory B cell numbers remained constant be- lived. However, current experimental evidence for this idea is tween 8 and 20 wk postimmunization, and based on short-term varied and at times contradictory. Yet, a clear definition of memory in vivo BrdU-labeling experiments estimated the t1/2 of mem- B cell life spans and the mechanisms regulating this process is ory B cells to be 8–10 wk. Given that the accepted t1/2 of naive critical for vaccine design and for developing improved strategies B cells is 7–8 wk (12–14), based on these results it is unclear for combating Ab-mediated pathologies. whether individual memory B cells possess substantially longer In people, numbers of Ag-specific memory B cells remain life spans than their naive counterparts. By contrast, Pape et al. relatively stable for .50 y after smallpox vaccination (6). How- (15) showed immunization of conventional inbred mice with ever, these results do not provide information on the life span of the protein PE induced the generation of long-lived IgM+ and by guest on September 24, 2021 individual cells. Consequently, it is not known whether long-term class-switched (IgG+) memory cells. However, whereas in this maintenance of such populations requires periodic input from system IgM+ memory B cells remained constant for upward of activated B cells, or whether particular clones come to dominate 500 d, class-switched cells decayed with exponential kinetics, memory pools over extended time frames. The former scenario is returning to preimmunization levels by 400 d (15). Why IgM consistent with the work of Barrington et al. (7) wherein persisting and class-switched memory cells might possess distinct t1/2 Ag appeared to promote the generation of nascent memory B cells remains to be determined. These results also appear to differ well after immunization. Similarly, others have proposed that with those of Schittek and Rajewsky (16), who showed that maintenance of serum Ab titers requires the slow, but consistent class-switched memory B cell pools are relatively stable over generation of plasma cells by Ag-activated memory B cells (8, 9). 8 wk. However, the latter workers did not examine decay rates These ideas are consistent with a model put forth earlier by Fearon for extended periods, or attempt to calculate t1/2 for individual et al. (10) proposing that memory B cells employ a stem cell-like cells within this pool. self-renewal program to continuously generate plasma cells. No- To resolve these issues, we employed a nontoxic pulse-chase tably, although each of these scenarios predicts that memory B cell labeling approach. This strategy exploits a tetracycline-regulated pools contain meaningful numbers of activated or recently acti- reporter allele encoding the chromatin protein histone 2B fused to GFP. This approach allowed us to establish decay rates for individual cells within established Ag-specific memory B cell Department of Pathology and Laboratory Medicine, University of Pennsylvania populations without concern for the toxic effects associated School of Medicine, Philadelphia, PA 19104 with extended exposure to DNA nucleotide analogs such as Received for publication June 15, 2015. Accepted for publication September 14, BrdU. To provide appropriate benchmarks for this system, we 2015. also determined decay rates for naive B cell populations. Our This work was supported by National Institutes of Health Grant R01-AI097590 (to results show that whereas naive follicular and marginal zone D.A.) and National Institutes of Health Training Grant T32CA009140 (to D.D.J.). B cells exhibit decay rates consistent with a t1/2 of 13–22 wk, Address correspondence and reprint requests to Dr. David Allman, University of + + Pennsylvania, 36th Street and Hamilton Walk, 230 John Morgan Building, Philadel- decay rates for IgM and IgG memory B cells were mark- phia, PA 19104-6082. E-mail address: [email protected] edly slower, revealing cellular t1/2 greater than the 2-y life Abbreviations used in this article: BV, Brilliant Violet; DOX, doxycycline; GC, span of the mouse. These data illustrate that, once established, germinal center; NP, (4-hydroxy-3-nitrophenyl)acetyl; TACI, transmembrane activa- Ag-specific memory B cell populations are remarkably stable tor and calcium-modulating cyclophilin ligand interactor. and highly enriched for quiescent and exceptionally long-lived Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 cells. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1501365 2 MEMORY B CELL LIFE SPAN Materials and Methods ligand interactor (TACI) were PE conjugates purchased from BioLegend. Mice and immunizations Flow cytometric acquisition was performed on a BD LSRII, and analyses were performed using FlowJo 8.8.6 (Tree Star). Multiple files per sample Adult C57BL/6 or C57BL/6-backcrossed Rosa26+/rtTA,Col1A1+/TetOP-H2B-GFP were concatenated prior to data analysis. Cells were sorted for cell culture mice were purchased from Jackson Laboratories and maintained in a with a four-laser FACSAria. specific pathogen-free facility at the University of Pennsylvania, in ac- cordance with institutional guidelines for animal care and welfare. Mice Cell culture were immunized i.p. with 50 mg (4-hydroxy-3-nitrophenyl)acetyl (NP)18- Sorted B cells were cultured for 2–3 d in RPMI 1640 supplemented with chicken g-globulin in alum. To induce transgene expression, mice were 10% FCS and glutamine, antibiotics, HEPES, and 2-ME before analysis maintained on drinking water containing 2 mg/ml doxycycline (DOX; by flow cytometry. LPS (Escherichia coli) was purchased from Sigma- Sigma-Aldrich) supplemented with 10 mg/ml sucrose. Aldrich and used at 10 mg/ml. Flow cytometry Estimation of cellular t1/2 Single-cell suspensions of splenocytes were prepared, depleted of RBCs by When possible, t1/2 for defined cell populations were calculated as fol- hypotonic lysis, and stained with optimal dilutions of the indicated Abs, as lows: t1/2 =(T3 log2)/ log (starting quantity/ending quantity), where T = described (17). All of the following reagents were obtained from eBio- elapsed time. science, unless noted otherwise: PerCP-eFluor710 anti-IgM (II/41); PE anti-CD23 (B3B4; BD Pharmingen); anti-CD138 (281-2; BD Pharmingen); PE-Texas Red anti-B220 (RA3-6B2); PE-Cy7 anti-CD21/35 (eBioBD9), Results anti-CD4 (GK1.5), anti-CD8a (53-6.7), anti–Gr-1 (RB6-8C5), anti-F4/80 Inclusion of the tetracycline analog DOX in the drinking water of (BM8), and anti-TER119 (BioLegend); allophycocyanin anti-CD93 Rosa26+/rtTA, Col1A1+/TetOP-H2B-GFP mice induces the expression (AA4.1); AlexaFluor700 anti-CD38 (90); allophycocyanin-Cy5.5 anti- of Histone2B-GFP fusion proteins. Once generated, Histone2B- Downloaded from CD19 (RM7719; Invitrogen); allophycocyanin-Cy7 anti-IgD (11-26c.2a; GFP proteins incorporate into the chromatin of most cells, BioLegend); and Brilliant Violet (BV; all from BioLegend), 605 anti-CD73 (TY/11.8), BV650 anti-CD80 (16-I0A1), BV785 anti-CD19 (6D5), and allowing the tracking of individual nondividing cells for at least biotin anti–PD-L2 (TY25; BioLegend).
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