IL-15 and IL-15 Receptor Selectively Regulate Differentiation of Common Mucosal Immune System-Independent B-1 Cells for IgA Responses

Hiroi, Takachika; Yanagita, Manabu; Ohta, Nobuaki; Sakaue, Gaku; Kiyono, Hiroshi

doi:10.4049/jimmunol.165.8.4329

Cited by 72 publications

(54 citation statements)

References 51 publications

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“…IL-2 has been shown to be essential to IgA expression in multiple species including cattle (38). IL-2 has been proposed to be an important factor in the terminal differentiation of sIgA ϩ B-2 cells whereas IL-15 has been shown to lead to the enhancement of IgA expression from B-1 but not B-2 cells in mice (39). Mucosal B-1 cell development into IgA-secreting cells has been linked to type 2 cytokines like IL-5.…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of a Novel Regulatory Factor: IgA-Inducing Protein

Austin

Haas

Naugler

et al. 2003

The Journal of Immunology

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IgA is the predominant Ig isotype in mucosal secretions and thus plays a pivotal role in host defense. The mechanisms by which IgA expression is regulated may differ among species and involve multiple pathways. Various cytokines and costimulators have been identified which regulate expression of this isotype, including IL-10, IL-2, vasoactive intestinal peptide, and TGF-β. We have tested a wide array of known factors, but only under very limited conditions do these factors mediate substantial IgA production in vitro from bovine B cells. In response to these findings, we generated a cDNA library in a mammalian expression vector from activated cells derived from bovine gut-associated lymphoid tissues (Peyer’s patch and mesenteric lymph node cells) as a source of soluble factor(s) that may regulate IgA production. We have identified a novel factor, IgA-inducing protein, which stimulates relatively high levels of IgA production in vitro following CD40 stimulation in coculture with IL-2. Our data suggest that IgA-inducing protein regulates IgA by acting as a switch or differentiation factor and is expressed in a variety of lymphoid and nonlymphoid tissues.

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Section: Discussionmentioning

confidence: 99%

Identification and Characterization of a Novel Regulatory Factor: IgA-Inducing Protein

Austin

Haas

Naugler

et al. 2003

The Journal of Immunology

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“…These antigen-sensitized cells leave the PP and contribute to the subsequent induction of Salmonella-specific IgA response in the distant intestinal LP by means of CMIS. In addition to the wellcharacterized CMIS-dependent IgA induction pathway, recent evidence suggests the presence of an additional IgA induction pathway that is independently operated from the PP-originated CMIS (13)(14)(15). Interestingly, it also has been reported that induction of intestinal mucosal IgA against the commensal bacteria was independent from T cell help and organized lymphoid tissue (16).…”

mentioning

confidence: 99%

Intestinal villous M cells: An antigen entry site in the mucosal epithelium

Jang

Kweon

Iwatani

et al. 2004

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

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T he huge intestinal surface area is physically protected by a layer of tightly joined epithelial cells, which prevent most enteric environmental antigens from penetrating the host (1). However, entry into the host is made possible by a special gateway, comprised of M cells, located over organized mucosal lymphoid follicles such as Peyer's patches (PP). The M cells, characterized by an irregular brush border and reduced glycocalyx, efficiently take up and transport a wide variety of macromolecules and microorganisms from the gut lumen to the inside of the PP (2-6), which contain all of the necessary lymphoid cells for the induction and regulation of antigen-specific IgA responses (7). However, the origin of M cells and the regulation of their development are not understood. A previous study (8) The common mucosal immune system (CMIS), which connects the inductive (e.g., PP) and effector (e.g., lamina propria; LP) sites, has been shown to be a central pathway for the induction of antigen-specific IgA immune responses in the gastrointestinal tract (7). For example, oral administration of Salmonella typhimurium leads to the transport of the bacterial antigen from the lumen of the intestinal tract into the PP by means of M cells for the initial priming of antigen-specific CD4 ϩ T cells and IgA-committed B cells (12). These antigen-sensitized cells leave the PP and contribute to the subsequent induction of Salmonella-specific IgA response in the distant intestinal LP by means of CMIS. In addition to the wellcharacterized CMIS-dependent IgA induction pathway, recent evidence suggests the presence of an additional IgA induction pathway that is independently operated from the PP-originated CMIS (13-15). Interestingly, it also has been reported that induction of intestinal mucosal IgA against the commensal bacteria was independent from T cell help and organized lymphoid tissue (16). Further, our recent study (17) has demonstrated that antigenspecific IgA antibody responses can be induced in the absence of PP. These studies imply the existence of a PP-independent mucosal immune pathway for dietary antigen and bacteria uptake.A recent study (18) has suggested that the invasion gene (SPI1)-deficient S. typhimurium can be disseminated from the intestinal epithelium to the systemic compartment in the absence of PPassociated M cells by means of the CD18-dependent pathway. Further, dendritic cells in the lamina propria of the small intestine expressing tight junction protein offer another possible antigen uptake site (19). Thus, intestinal DCs are capable of extending dendrites to the lumen side by opening the tight junction. However, the exact mechanism for inducing Ag-specific immune responses independently of PP requires further elucidation.In this study, we have discovered intestinal villous M cells, which serve as an antigen gateway for the sampling of gut bacteria and subsequent induction of Ag-specific immune responses in a PPindependent manner. These lines of study are crucial for understanding the mechanisms of antige...

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“…A report suggested that IL-15 promoted IgA synthesis at definite mucosal sites, but its impact on 'natural' IgM production by B-1 cells remains unresolved. 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.…”

Section: Il-15 Augmented Igm and Iga Expressionmentioning

confidence: 99%

“…19 Although IL-15 has several important and well-documented roles in regulating T-cell function, including restraining tumorigenesis, the interplay between IL-15 and B-1a cells has received little attention. A few studies have demonstrated that IL-15 stimulates B cell proliferation and immunoglobulin synthesis, 20,21 indicating that the role of the cytokine in regulating B-1a cells could be important because these cells are the key players of mucosal immunity.…”

Section: Introductionmentioning

confidence: 99%

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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IL-15 and IL-15 Receptor Selectively Regulate Differentiation of Common Mucosal Immune System-Independent B-1 Cells for IgA Responses

Cited by 72 publications

References 51 publications

Identification and Characterization of a Novel Regulatory Factor: IgA-Inducing Protein

Identification and Characterization of a Novel Regulatory Factor: IgA-Inducing Protein

Intestinal villous M cells: An antigen entry site in the mucosal epithelium

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

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