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Homeostatic and Activated Conditions Cell The Journal of Immunology Dynamics of the Splenic Innate-like CD19+CD45Rlo Cell Population from Adult Mice in Homeostatic and Activated Conditions Bele´n de Andre´s,*,1 Carmen Prado,* Beatriz Palacios,* Mario Alı´a,* Sharmili Jagtap,† Natalia Serrano,† Isabel Cortegano,* Miguel Angel R. Marcos,† and Maria Luisa Gaspar*,1 In the adult spleen, CD19+CD45R2/lo (19+45Rlo) lymphocytes of embryonic origin exist as a distinct population to that of the conventional B cell lineage. These cells display a plasmablast phenotype, and they spontaneously secrete IgG1 and IgA, whereas the bone marrow population of 19+45Rlo cells contains B1 progenitors. In this study, we show that 19+45Rlo cells are also present in Peyer’s patches and in the spleen throughout the life span of wild-type mice, beginning at postnatal day 7. Although this population is heterogeneous, the surface phenotype of most of these cells distinguishes them from follicular, transitional, marginal zone, and B1 cells. In CBA/CaHN mice, few 19+45Rlo cells were detected at postnatal day 7, and none was observed in the adult spleen. Splenic 19+45Rlo cells exhibited homeostatic BrdU uptake in vivo and actively transcribed cell cycle genes. When trans- ferred to immunodeficient RAG22/2gchain2/2 recipient mice, 19+45Rlo cells survived and differentiated into IgG1– and IgA– plasma cells. Moreover, in vitro stimulation of splenic 19+45Rlo cells with LPS, CpG, BAFF/IL4, and CD40/IL4 induced cell proliferation, IgG1/IgA secretion and the release of IL-10, suggesting a potential immunoregulatory role for this subset of innate- like B cells. The Journal of Immunology, 2012, 189: 2300–2308. n peripheral organs, lymphocytes shape the adaptive immune scribed, such as age-associated B cells (ABCs) (6, 7), gut-associated system responses by performing specialized functions, and B cells (8), and innate response activator (IRA) cells (9), which are I they can be categorized as either innate-like or conventional implicated in autoimmune disorders and the responses to microbial adaptive cells. Innate-like B cells are B1 cells and marginal zone infection. (MZ) B cells, whereas the adaptive branch mainly contains fol- The peripheral B cell compartments are maintained by a series of licular B (FoB) cells. B-1 and MZ cells share some characteristic coordinated mechanisms. The new immature precursors compete for features such as the oligoclonality of their BCRs (1, 2), Ag- limited resources, and they must pass through sequential BCR independent selection (3), their distribution in particular niches, checkpoints, which limit the number of progenitors that successfully by guest on October 1, 2021. Copyright 2012 Pageant Media Ltd. a preactivation status that is responsible for their rapid multi- differentiate (10). Furthermore, the survival and differentiation specific responses (4), and their participation in maintaining ho- of cells are conditioned by their responses to BCR- and TLR- meostasis and in the initial phases of the immune response (5). activating signal pathways (11) and by their access to selected Recently, several new innate like B lymphocytes have been de- cytokines and niches (12). Soluble factors such as BAFF and a proliferation-inducing ligand (APRIL) provide survival and prolif- erative signals (13), and they induce isotype switching in mature B *Centro Nacional de Microbiologı´a, Instituto de Salud Carlos III, Majadahonda, (MB) cells (14). Activated B cells mediate immune regulation 28220 Madrid, Spain; and †Centro de Biologı´a Molecular Severo Ochoa, Consejo through the secretion of Igs and a wide range of cytokines, all of Superior de Investigaciones Cientı´ficas, Campus de Cantoblanco, 28049 Madrid, which modulate T cell activity (15–17). Spain http://classic.jimmunol.org In the mouse embryo, studies of the development of hemato- 1B.d.A. and M.L.G. contributed equally to this study. poietic programs revealed the first unilineage B cell progenitor Received for publication January 19, 2012. Accepted for publication June 27, 2012. to be CD19+AA4.1+Pax-5+, which lacks the CD45R/B220 This work was supported by grants from the Fondo de Investigaciones Sanitarias phosphatase (18, 19). In mouse bone marrow (BM), the CD19+ (MPY 1374/08), the Comunidad Auto´noma de Madrid (SAL-0304-2006), and the 2/lo + lo + Ministerio de Ciencia e Innovacio´n (SAF2007-65265 and SAF2009-12596). N.S. CD45R (19 45R ) cell population (hereafter referred to as 19 received a fellowship from the Centro de Biologı´a Molecular Severo Ochoa, I.C. 45Rlo) is an immature population containing B1 progenitors (20– received a fellowship from the Ministerio de Ciencia e Innovacio´n, B.P. received + lo Downloaded from a fellowship from the Fondo de Investigaciones Sanitarias, and S.J. received a fellow- 22). We previously described the presence of 19 45R cells of ship from the Comunidad Auto´noma de Madrid. The Centro de Biologı´a Molecular, embryonic origin in the spleen of juvenile and adult mice (23). Severo Ochoa, receives institutional funding from the Fundacio´n Ramo´n Areces. These cells have a singular phenotype (CD52CD11b2CD21lo Address correspondence and reprint requests to Dr. Bele´n de Andre´s, Unidad de CD232IgD2) with bimodal expression of IgM and spontaneously Inmunobiologı´a, Centro Nacional de Microbiologı´a, Instituto de Salud Carlos III, Carretera de Majadahonda a Pozuelo km 2,5, Majadahonda, 28220 Madrid, Spain. release IgG1 and IgA. E-mail address: [email protected] In the current study, we analyzed the homeostatic behavior and + lo Abbreviations used in this article: ABC, age-associated B cell; APRIL, a prolifera- maintenance of embryo-derived 19 45R cells, as well as their + lo tion-inducing ligand; BM, bone marrow; btk, Bruton’s tyrosine kinase; CT, threshold capacity for in vitro activation. We show that 19 45R cells are cycle; FoB, follicular B; IL12p70, p70 subunit of IL-12; IRA, innate response acti- vator; LN, lymph node; MB, mature B; MZ, marginal zone; PB, peripheral blood; present in the spleen and Peyer’s patches (PP) and as circulating PC, plasma cell; PD, postnatal day; PP, Peyer’s patches; PWC, peritoneal washed cells throughout the life span of the mouse and that the cell + lo + 2/lo 2/2 2/2 2/2 cell; 19 45R , CD19 CD45R ; Rag2g ,RAG2 gchain ; RT-qPCR, quan- number in the spleen is tightly controlled until 1 y of age. The titative real-time PCR; T1, transitional 1. surface phenotype of this cell type distinguishes them from tran- Copyright Ó 2012 by The American Association of Immunologists, Inc. 0022-1767/12/$16.00 sitional B cells, B1 cells, IRA B cells, and ABCs, although like B1 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1200224 The Journal of Immunology 2301 cells, they are Bruton’s tyrosine kinase (btk) dependent. 19+45Rlo pression of cell cycle genes was analyzed in samples using the mouse cell 2 cells actively express cell-cycling genes and exhibit a high rate of cycle RT Profiler PCR array (SABiosciences). The PCR array data proliferation under homeostatic conditions in vivo. When trans- analysis web portal (http://www.SABiosciences.com/pcrarraydataanalysis. php) was used to calculate the threshold cycle (C ) values and to obtain ferred to immunodeficient RAG22/2gchain2/2 (Rag2g2/2) mice, T DCT values normalized to those of housekeeping genes. To determine the a population of IgG1/IgA-secreting 19+45Rlo cells was established differences in relative expression between B cell populations, comparative 2 and maintained in the spleen. Moreover, 19+45Rlo cells responded analyses were performed (2 DDCT) using the PCR Array Data Analysis to stimulation with TLR ligand and BAFF/IL4 by undergoing Software (SABiosciences). + isotype class switching and secreting IL-10. We conclude that 19 Quantitative real-time PCR 45Rlo cells constitute an activated component of the innate-like B cell population with an exceptional ability to release IgG1 and Quantitative real-time PCR (RT-qPCR) was performed as previously de- IgA and promising immunoregulatory properties based on their scribed (23) with the following IL-10 primers: sense, 59-TCGATTTCTC- CCCTGTGA-39; and antisense, 59-GACACCTTGGTCTTGGAGCT-39. production of IL-10. DCT values normalized with the HPRT gene were calculated. Materials and Methods ELISAs Mice ELISAs were performed using sera collected from transferred mice and in vitro culture supernatants, as described previously (25). Standard curves BALB/c, C57BL/6, C57BL6.Ly5.1, CBA/CaHN (CBA/N), CBA/CaJ, and 2 2 for each isotype were generated using the following purified myeloma Rag2g / mice were bred and maintained in animal facilities at the proteins or Abs: IgM (clone G155-228; BD Biosciences), IgG1 (clone Instituto de Salud Carlos III and the Centro de Biologı´a Molecular Severo 4.19) (26), and IgA (clone M18-254; BD Biosciences). GraphPad Prism Ochoa. Animals were sacrificed by cervical dislocation, and cell suspen- 4.0 software was used to calculate Ig concentrations. sions were obtained subsequently from the lymphoid organs, peripheral blood (PB), and peritoneal exudates (peritoneal washed cells [PWC]). All CFSE labeling procedures were carried in accordance with approved protocols and guidelines established by the Institutional Animal Care and Use Com- Purified 19+45Rlo and 19+45R+ cells were incubated in darkness at a den- mittees of the Instituto de Salud Carlos III and the Centro de Biologı´a sity of 105 cells/100 mlin5mM CFSE dissolved in PBS/0.1% BSA. After Molecular Severo Ochoa. 15 min at room temperature, the cells were washed twice before being used for in vitro stimulation. Flow cytometry and cell sorting B cell cultures Single-cell suspensions were prepared in staining buffer (2.5% FCS in Dulbecco’s PBS; Biowhittaker, Lonza Group, Basel, Switzerland), and CFSE-labeled cells (40,000 cells/well) were plated in flat-bottom 96-well nonspecific binding was blocked with Fc block (BD Biosciences, San Jose, culture plates (BD Biosciences) in RPMI 1640 supplemented with 10% CA).
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