Abstract
Lipopolysaccharide (LPS) from gram-negative bacteria activates B cells, enabling them to proliferate and differentiate into plasma cells. This response is critically dependent on the expression of TLR4; but other genes, such as RP105 and MHC class II, have also been shown to contribute to B cell LPS response. Here, we have evaluated the role of genetic control of the B cell response to LPS at the single cell level. We compared the response to LPS of peritoneal cavity (PEC) and splenic B cells on the BALB/c genetic background (LPS-low responder) to those on the C57BL/6J background (LPS-high responder) and their F1 progeny (CB6F1). Both PEC and splenic B cells from B6 exhibited 100% clonal growth in the presence of LPS; whereas, BALB/c PEC and splenic B cells achieved only 50% and 23% clonal growth, respectively. Adding CpG to the LPS stimulus pushed PEC B cell clonal growth in the low responder strain BALB/c up to 90%, showing that the nonresponse to LPS is a specific effect. Surprisingly, PEC B cells on the F1 background behaved as high responders, while splenic B cells behaved as low responders to LPS. The data presented here reveals a previous unsuspected behavior in the genetic control of the B cell response to LPS with an opposing impact in splenic versus peritoneal cavity B cells. These results suggest the existence of an, as yet, unidentified genetic factor exclusively expressed by coelomic B cells that contributes to the control of the LPS signaling pathway in the B lymphocyte.
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References
Andersson J, Coutinho A, Lernhardt W, Melchers F (1977) Clonal growth and maturation to immunoglobulin secretion in vitro of every growth-inducible B lymphocyte. Cell 10:27–34
Briles DE, Nahm M, Schroer K, Davie J, Baker P, Kearney J, Barletta R (1981) Antiphosphocholine antibodies found in normal mouse serum are protective against intravenous infection with type 3 streptococcus pneumoniae. J Exp Med 153:694–705
Casali P, Schettino EW (1996) Structure and function of natural antibodies. Curr Top Microbiol Immunol 210:167–179
Collins LS, Dorshkind K (1987) A stromal cell line from myeloid long-term bone marrow cultures can support myelopoiesis and B lymphopoiesis. J Immunol 138:1082–1087
da Silva Correia J, Soldau K, Christen U, Tobias PS, Ulevitch RJ (2001) Lipopolysaccharide is in close proximity to each of the proteins in its membrane receptor complex. transfer from CD14 to TLR4 and MD-2. J Biol Chem 276:21129–21135
Desiderio S (1997) Role of Btk in B cell development and signaling. Curr Opin Immunol 9:534–540
Herzenberg LA (1989) Toward a layered immune system. Cell 59:953–954
Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y, Takeda K, Akira S (1999) Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the LPS gene product. J Immunol 162:3749–3752
Kalis C, Kanzler B, Lembo A, Poltorak A, Galanos C, Freudenberg MA (2003) Toll-like receptor 4 expression levels determine the degree of LPS-susceptibility in mice. Eur J Immunol 33:798–805
Kawai T, Akira S (2007) TLR signaling. Semin Immunol 19:9
Lam KP, Stall AM (1994) Major histocompatibility complex class II expression distinguishes two distinct B cell developmental pathways during ontogeny. J Exp Med 180:507–516
Martin F, Kearney JF (2002) Marginal-zone B cells. Nat Rev Immunol 2:323–335
Medzhitov R (2001) Toll-like receptors and innate immunity. Nat Rev Immunol 1:135–145
Meyer-Bahlburg A, Andrews SF, Yu KO, Porcelli SA, Rawlings DJ (2008) Characterization of a late transitional B cell population highly sensitive to BAFF-mediated homeostatic proliferation. J Exp Med 205:155–168
Montecino-Rodriguez E, Leathers H, Dorshkind K (2006) Identification of a B-1 B cell-specified progenitor. Nat Immunol 7:293–301
Nagai Y, Kobayashi T, Motoi Y, Ishiguro K, Akashi S, Saitoh S, Kusumoto Y, Kaisho T, Akira S, Matsumoto M, Takatsu K, Miyake K (2005) The radioprotective 105/MD-1 complex links TLR2 and TLR4/MD-2 in antibody response to microbial membranes. J Immunol 174:7043–7049
Ogata H, Su I, Miyake K, Nagai Y, Akashi S, Mecklenbrauker I, Rajewsky K, Kimoto M, Tarakhovsky A (2000) The toll-like receptor protein RP105 regulates lipopolysaccharide signaling in B cells. J Exp Med 192:23–29
Oliver AM, Martin F, Kearney JF (1999) IgMhighCD21high lymphocytes enriched in the splenic marginal zone generate effector cells more rapidly than the bulk of follicular B cells. J Immunol 162:7198–7207
Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282:2085–2088
Rodo J, Goncalves LA, Demengeot J, Coutinho A, Penha-Goncalves C (2006) MHC class II molecules control murine B cell responsiveness to lipopolysaccharide stimulation. J Immunol 177:4620–4626
Sato S, Ono N, Steeber DA, Pisetsky DS, Tedder TF (1996) CD19 regulates B lymphocyte signaling thresholds critical for the development of B-1 lineage cells and autoimmunity. J Immunol 157:4371–4378
Sporri R, Reis e Sousa C (2005) Inflammatory mediators are insufficient for full dendritic cell activation and promote expansion of CD4+ T cell populations lacking helper function. Nat Immunol 6:163–170
Acknowledgments
We would like to thank JF Kearney for BC8 and C.B-17 mice. This work was supported by CNPq, FAPERJ, and FINEP, and in part by AI048115 (HWS) and AI078449 (HWS). The authors declare that they have no competing financial interests.
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Vale, A.M., Hayashi, E., Granato, A. et al. Genetic control of the B cell response to LPS: opposing effects in peritoneal versus splenic B cell populations. Immunogenetics 62, 41–48 (2010). https://doi.org/10.1007/s00251-009-0404-9
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DOI: https://doi.org/10.1007/s00251-009-0404-9