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Microbe-dependent CD11b+ IgA+ plasma cells mediate robust early-phase intestinal IgA responses in mice.

Kunisawa J, Gohda M, Hashimoto E, Ishikawa I, Higuchi M, Suzuki Y, Goto Y, Panea C, Ivanov II, Sumiya R, Aayam L, Wake T, Tajiri S, Kurashima Y, Shikata S, Akira S, Takeda K, Kiyono H - Nat Commun (2013)

Bottom Line: CD11b(+) IgA(+) plasma cells require the lymphoid structure of Peyer's patches, produce more IgA than CD11b(-) IgA(+) plasma cells, proliferate vigorously, and require microbial stimulation and IL-10 for their development and maintenance.These features allow CD11b(+) IgA(+) plasma cells to mediate early-phase antigen-specific intestinal IgA responses induced by oral immunization with protein antigen.These findings reveal the functional diversity of IgA(+) plasma cells in the murine intestine.

View Article: PubMed Central - PubMed

Affiliation: Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. kunisawa@nibio.go.jp

ABSTRACT
Intestinal plasma cells predominantly produce immunoglobulin (Ig) A, however, their functional diversity remains poorly characterized. Here we show that murine intestinal IgA plasma cells can be newly classified into two populations on the basis of CD11b expression, which cannot be discriminated by currently known criteria such as general plasma cell markers, B cell origin and T cell dependence. CD11b(+) IgA(+) plasma cells require the lymphoid structure of Peyer's patches, produce more IgA than CD11b(-) IgA(+) plasma cells, proliferate vigorously, and require microbial stimulation and IL-10 for their development and maintenance. These features allow CD11b(+) IgA(+) plasma cells to mediate early-phase antigen-specific intestinal IgA responses induced by oral immunization with protein antigen. These findings reveal the functional diversity of IgA(+) plasma cells in the murine intestine.

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CD11b+ IgA+ cells are proliferating cells.(a) mRNA was purified from small intestinal CD11b+ and CD11b− IgA+ cells and used for microarray analysis. Data related to the cell cycle and proliferation are shown. Data are representative of two independent experiments. (b) Mice were treated with BrdU, and uptake of BrdU by CD11b+ and CD11b− IgA+ cells was determined by flow cytometry. Data are representative of four independent experiments. (c) Cells were isolated from the intestinal lamina propria of mice receiving CPM to analyse CD11b+ IgA+ cells. Similar results were obtained from four separate experiments. Graphs show data from individual mice. Statistical analyses were performed with Mann–Whitney’s U-test.
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f4: CD11b+ IgA+ cells are proliferating cells.(a) mRNA was purified from small intestinal CD11b+ and CD11b− IgA+ cells and used for microarray analysis. Data related to the cell cycle and proliferation are shown. Data are representative of two independent experiments. (b) Mice were treated with BrdU, and uptake of BrdU by CD11b+ and CD11b− IgA+ cells was determined by flow cytometry. Data are representative of four independent experiments. (c) Cells were isolated from the intestinal lamina propria of mice receiving CPM to analyse CD11b+ IgA+ cells. Similar results were obtained from four separate experiments. Graphs show data from individual mice. Statistical analyses were performed with Mann–Whitney’s U-test.

Mentions: We next performed a gene microarray analysis to assess the uniqueness of CD11b+ IgA+ PCs in the iLP. Gene ontology enrichment score computation analysis showed that the activity of cell-cycle-associated pathways was higher in CD11b+ IgA+ PCs than in CD11b− IgA+ PCs (Supplementary Table S1). Consistent with this finding, higher expression of cell-cycle-associated genes was noted in CD11b+ IgA+ PCs than in CD11b− IgA+ PCs; these genes included members of the cell division cycle family (Fig. 4a and Supplementary Table S2). In line with this, these cells expressed higher levels of the proliferation marker Ki67 than did CD11b− IgA+ PCs (Fig. 4a and Supplementary Table S2). Additionally, CD11b+ IgA+ PCs showed greater uptake of bromodeoxyuridine (BrdU) than did CD11b− IgA+ PCs (Fig. 4b). CD11b+ IgA+ PCs were preferentially removed by treatment with cyclophosphamide (CPM), which selectively targets proliferating cells (Fig. 4c). These data collectively suggested that CD11b+ IgA+ PCs possessed greater proliferating activity than did CD11b− IgA+ PCs in the iLP.


Microbe-dependent CD11b+ IgA+ plasma cells mediate robust early-phase intestinal IgA responses in mice.

Kunisawa J, Gohda M, Hashimoto E, Ishikawa I, Higuchi M, Suzuki Y, Goto Y, Panea C, Ivanov II, Sumiya R, Aayam L, Wake T, Tajiri S, Kurashima Y, Shikata S, Akira S, Takeda K, Kiyono H - Nat Commun (2013)

CD11b+ IgA+ cells are proliferating cells.(a) mRNA was purified from small intestinal CD11b+ and CD11b− IgA+ cells and used for microarray analysis. Data related to the cell cycle and proliferation are shown. Data are representative of two independent experiments. (b) Mice were treated with BrdU, and uptake of BrdU by CD11b+ and CD11b− IgA+ cells was determined by flow cytometry. Data are representative of four independent experiments. (c) Cells were isolated from the intestinal lamina propria of mice receiving CPM to analyse CD11b+ IgA+ cells. Similar results were obtained from four separate experiments. Graphs show data from individual mice. Statistical analyses were performed with Mann–Whitney’s U-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3644083&req=5

f4: CD11b+ IgA+ cells are proliferating cells.(a) mRNA was purified from small intestinal CD11b+ and CD11b− IgA+ cells and used for microarray analysis. Data related to the cell cycle and proliferation are shown. Data are representative of two independent experiments. (b) Mice were treated with BrdU, and uptake of BrdU by CD11b+ and CD11b− IgA+ cells was determined by flow cytometry. Data are representative of four independent experiments. (c) Cells were isolated from the intestinal lamina propria of mice receiving CPM to analyse CD11b+ IgA+ cells. Similar results were obtained from four separate experiments. Graphs show data from individual mice. Statistical analyses were performed with Mann–Whitney’s U-test.
Mentions: We next performed a gene microarray analysis to assess the uniqueness of CD11b+ IgA+ PCs in the iLP. Gene ontology enrichment score computation analysis showed that the activity of cell-cycle-associated pathways was higher in CD11b+ IgA+ PCs than in CD11b− IgA+ PCs (Supplementary Table S1). Consistent with this finding, higher expression of cell-cycle-associated genes was noted in CD11b+ IgA+ PCs than in CD11b− IgA+ PCs; these genes included members of the cell division cycle family (Fig. 4a and Supplementary Table S2). In line with this, these cells expressed higher levels of the proliferation marker Ki67 than did CD11b− IgA+ PCs (Fig. 4a and Supplementary Table S2). Additionally, CD11b+ IgA+ PCs showed greater uptake of bromodeoxyuridine (BrdU) than did CD11b− IgA+ PCs (Fig. 4b). CD11b+ IgA+ PCs were preferentially removed by treatment with cyclophosphamide (CPM), which selectively targets proliferating cells (Fig. 4c). These data collectively suggested that CD11b+ IgA+ PCs possessed greater proliferating activity than did CD11b− IgA+ PCs in the iLP.

Bottom Line: CD11b(+) IgA(+) plasma cells require the lymphoid structure of Peyer's patches, produce more IgA than CD11b(-) IgA(+) plasma cells, proliferate vigorously, and require microbial stimulation and IL-10 for their development and maintenance.These features allow CD11b(+) IgA(+) plasma cells to mediate early-phase antigen-specific intestinal IgA responses induced by oral immunization with protein antigen.These findings reveal the functional diversity of IgA(+) plasma cells in the murine intestine.

View Article: PubMed Central - PubMed

Affiliation: Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. kunisawa@nibio.go.jp

ABSTRACT
Intestinal plasma cells predominantly produce immunoglobulin (Ig) A, however, their functional diversity remains poorly characterized. Here we show that murine intestinal IgA plasma cells can be newly classified into two populations on the basis of CD11b expression, which cannot be discriminated by currently known criteria such as general plasma cell markers, B cell origin and T cell dependence. CD11b(+) IgA(+) plasma cells require the lymphoid structure of Peyer's patches, produce more IgA than CD11b(-) IgA(+) plasma cells, proliferate vigorously, and require microbial stimulation and IL-10 for their development and maintenance. These features allow CD11b(+) IgA(+) plasma cells to mediate early-phase antigen-specific intestinal IgA responses induced by oral immunization with protein antigen. These findings reveal the functional diversity of IgA(+) plasma cells in the murine intestine.

Show MeSH
Related in: MedlinePlus