Antigen-specific B-1a antibodies induced by<i>Francisella tularensis</i>LPS provide long-term protection against<i>F. tularensis</i>LVS challenge

Cole, Leah E.; Yang, Yang; Elkins, Karen L.; Fernandez, Ellen T.; Qureshi, Nilofer; Shlomchik, Mark J.; Herzenberg, Leonard A.; Herzenberg, Leonore A.; Vogel, Stefanie N.

doi:10.1073/pnas.0813411106

Cited by 102 publications

(147 citation statements)

References 33 publications

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“…Thus, FtL immunization of xid mice does not result in expanded anti-FtL B-1a (<0.01% of splenic and PerC B cells) and does not induce production of serum anti-FtL. This response failure is consistent with our previous demonstration that FtL immunization of xid mice does not protect against subsequent lethal Ft LVS challenge (19).…”

supporting

confidence: 80%

“…Furthermore, anti-FtL B-1a disappear from the spleen within 1 wk of immunization (19), clearly before the time when GC usually starts developing (27)(28)(29)(30). Finally, B-cell lymphoma 6 (BCL6) up-regulation, a hallmark for GC B cells (26,31,32), is not detected on anti-FtL B-1a (Fig.…”

mentioning

confidence: 97%

“…Studies here and in a companion article (4) together show that the B-1a-mediated protection that FtL priming induces against lethal Ft LVS challenge (19) is accompanied by induction of antiFtL B-1a primary responses and, importantly, by induction of anti-FtL B-1a memory cells that persist indefinitely in PerC (but not elsewhere) and remain ready to respond to FtL rechallenge under appropriate conditions. Activation-induced cytidine deaminase (AID)-dependent isotype switching occurs during development of a proportion of these FtL-specfic B-1a memory cells.…”

mentioning

confidence: 99%

“…However, B-1a are clearly known to produce specific antibody responses to certain antigens, including phosphorylcholine (14-16) and α1,3 dextran (17, 18). Most recently, foreshadowing studies presented here, we have shown that immunization with FtL, an atypical LPS isolated from Ft LVS, induces B-1a with FtL-binding IgM receptors to appear in spleen and to produce anti-FtL IgM primary antibody responses that protect against lethal Ft LVS challenge (19,20). Consistent with B-1a mediating this protection, FtL priming does not similarly protect Bruton's tyrosine kinase (Btk)-mutant (xid) mice, which have B-1b but lack B-1a (21)(22)(23).…”

mentioning

confidence: 99%

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Antigen-specific antibody responses in B-1a and their relationship to natural immunity

Yang

Ghosn

Cole

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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B-1a cells are primarily thought of as natural antibody-producing cells. However, we now show that appropriate antigenic stimulation induces IgM and IgG B-1a antibody responses and long-lived T-independent antigen-specific B-1a memory that differs markedly from canonical B-2 humoral immunity. Thus, we show here that in the absence of inflammation, priming with glycolipid (FtL) from Francisella tularensis live vaccine strain induces splenic FtL-specific B-1a to mount dominant IgM and activation-induced cytidine deaminase-dependent IgG anti-FtL responses that occur within 3-5 d of FtL priming and fade within 1 wk to natural antibody levels that persist indefinitely in the absence of secondary FtL immunization. Equally surprising, FtL priming elicits long-term FtL-specific B-1a memory cells (IgM>>IgG) that migrate rapidly to the peritoneal cavity and persist there indefinitely, ready to respond to appropriately administrated secondary antigenic stimulation. Unlike B-2 responses, primary FtL-specific B-1a responses and establishment of persistent FtL-specific B-1a memory occur readily in the absence of adjuvants, IL-7, T cells, or germinal center support. However, in another marked departure from the mechanisms controlling B-2 memory responses, rechallenge with FtL in an inflammatory context is required to induce B-1a secondary antibody responses. These findings introduce previously unexplored vaccination strategies for pathogens that target the B-1a repertoire.B-1 | memory B cells | vaccine

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supporting

confidence: 80%

mentioning

confidence: 97%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Antigen-specific antibody responses in B-1a and their relationship to natural immunity

Yang

Ghosn

Cole

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…21 The immunization of animals with LPS of Francisella tularensis live vaccine strain (Ft LVS) showed protection against attenuated Ft LVS in which opsonizing IgM specifically derived from B-1a cells had played an important role. 41 Our data show that IL-15, which is expressed by enterocytes and found at the mucosal surfaces of the intestinal epithelium, directly augments IgM and IgA production. The upregulation of IgM by the cytokine suggests that IL-15 and B-1a cell function in close association to maintain the levels of IgM, a characteristic feature of these cells.…”

Section: Il-15 Augmented Igm and Iga Expressionmentioning

confidence: 82%

IL-15 temporally reorients IL-10 biased B-1a cells toward IL-12 expression

et al. 2015

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Interleukin (IL)-15 is known to strongly modulate T-cell function; however, its role in controlling mucosal immunity, including its ability to modulate B-1a cell activity, remains to be elucidated. Here, we show that IL-15 upregulates activation molecules and the costimulatory molecule CD80 on viable B-1a cells. Cell activation was accompanied by the depletion of sialic acid-binding immunoglobulin-like lectin (Siglec)-G, an inhibitor of cell activation that is present on B-1a cells. The IL-15 receptor CD122 was stimulated on B-1a cells by the cytokine showing its direct involvement in IL-15-mediated responses. IL-10 is responsible for the long term survival of B-1a cells in culture, which is initially promoted by IL-15. The upregulation of IL-10 was followed by the appearance of suppressor of cytokine signaling (SOCS)1 in the presence of IL-15 and the loss of IL-10. This resulted in the cells switching to IL-12 expression. This anti-inflammatory to pro-inflammatory shift in the B-1a cell character was independent of the cell-specific marker CD5, which remained highly expressed throughout the in vitro life of the cells. The presence of the immunosuppressive receptor programmed cell death (PD)-1 and its ligand PD-L2 were features of a predominantly IL-10 response. PD-1 and PD-L2 can mediate juxtacrine signaling. However, the abrogation of PD-1 and its ligand was observed when the cells expressed IL-12. This demonstrates an inverse relationship between the receptor and ligand and the pro-inflammatory cytokine. The induction of IgM and IgA, which can play pivotal roles in mucosal immunity, was promoted in the presence of IL-15. Collectively, the data implicate IL-15 as the master cytokine that induces B-1a cells to mount a mucosal immune response. Cellular & Molecular Immunology

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Purification and Immune Phenotyping of B-1 Cells from Body Cavities of Mice

Yenson¹,

Baumgarth²

2021

Methods in Molecular Biology

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Antigen-specific B-1a antibodies induced byFrancisella tularensisLPS provide long-term protection againstF. tularensisLVS challenge

Cited by 102 publications

References 33 publications

Antigen-specific antibody responses in B-1a and their relationship to natural immunity

Antigen-specific antibody responses in B-1a and their relationship to natural immunity

IL-15 temporally reorients IL-10 biased B-1a cells toward IL-12 expression

Purification and Immune Phenotyping of B-1 Cells from Body Cavities of Mice

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