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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 require the lymphoid structure of Peyer’s patches.(a) Mice were treated with FTY720 every day for 5 days. The day after the final treatment, the proportions of CD11b+ and CD11b− IgA+ cells were measured by flow cytometry. Data are presented as means±s.d. from four mice. Similar results were obtained from three separate experiments. (b) Proportions of CD11b+and CD11b− IgA+ cells in the iLP of WT and TCRβδ KO mice were measured by flow cytometry. Data are presented as means±s.d. from four mice. Similar results were obtained from three separate experiments. (c) After three oral immunizations with OVA plus cholera toxin, cells were isolated from the iLP and used in an ELISPOT assay to enumerate OVA-specific IgA AFCs. In some groups of mice, CD11b+ or CD11b− IgA+ cells were depleted by cell sorting before application of ELISPOT assay. Phosphorylcholine-specific IgA AFCs were measured. Graphs show data from individual mice, and bars indicate median. Statistical analyses were performed with Mann–Whitney’s U-test. (d) Mononuclear cells were isolated from the iLP of Peyer’s patch (PP)-normal (control Ab) and - (anti-IL-7Rα Ab) mice for analysis of IgA and CD11b expression by flow cytometry. Graphs show data from individual mice. Statistical analyses were performed with Mann–Whitney’s U-test. (e) Mononuclear cells were isolated from PPs for analysis of CD11b+ and CD11b− IgA+ cells by flow cytometry. Similar results were obtained from three separate experiments.
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f3: CD11b+ IgA+ cells require the lymphoid structure of Peyer’s patches.(a) Mice were treated with FTY720 every day for 5 days. The day after the final treatment, the proportions of CD11b+ and CD11b− IgA+ cells were measured by flow cytometry. Data are presented as means±s.d. from four mice. Similar results were obtained from three separate experiments. (b) Proportions of CD11b+and CD11b− IgA+ cells in the iLP of WT and TCRβδ KO mice were measured by flow cytometry. Data are presented as means±s.d. from four mice. Similar results were obtained from three separate experiments. (c) After three oral immunizations with OVA plus cholera toxin, cells were isolated from the iLP and used in an ELISPOT assay to enumerate OVA-specific IgA AFCs. In some groups of mice, CD11b+ or CD11b− IgA+ cells were depleted by cell sorting before application of ELISPOT assay. Phosphorylcholine-specific IgA AFCs were measured. Graphs show data from individual mice, and bars indicate median. Statistical analyses were performed with Mann–Whitney’s U-test. (d) Mononuclear cells were isolated from the iLP of Peyer’s patch (PP)-normal (control Ab) and - (anti-IL-7Rα Ab) mice for analysis of IgA and CD11b expression by flow cytometry. Graphs show data from individual mice. Statistical analyses were performed with Mann–Whitney’s U-test. (e) Mononuclear cells were isolated from PPs for analysis of CD11b+ and CD11b− IgA+ cells by flow cytometry. Similar results were obtained from three separate experiments.

Mentions: CD11b+ IgA+ PCs expressed CD18 (Supplementary Fig. S4), which associates with CD11b and acts as a ligand for intercellular adhesion molecule-1 (ICAM-1)24. As ICAM-1 is an endothelial adhesion molecule that regulates cell trafficking2425, we considered that CD11b+ IgA+ PCs were recent emigrants from IgA-inductive tissues (for example, PPs and PerC) and had migrated into the iLP. To test this possibility, we employed FTY720 to inhibit the trafficking of IgA-committed B cells from PPs and PerC into the iLP. As we previously reported1113, FTY720 treatment reduced the numbers of intestinal IgA+ PCs, but the effect was not specific to CD11b+ IgA+ PCs (Fig. 3a). These data suggested that CD11b+ IgA+ PCs were not recent emigrants from IgA inductive tissues (for example, PPs and PerC).


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 require the lymphoid structure of Peyer’s patches.(a) Mice were treated with FTY720 every day for 5 days. The day after the final treatment, the proportions of CD11b+ and CD11b− IgA+ cells were measured by flow cytometry. Data are presented as means±s.d. from four mice. Similar results were obtained from three separate experiments. (b) Proportions of CD11b+and CD11b− IgA+ cells in the iLP of WT and TCRβδ KO mice were measured by flow cytometry. Data are presented as means±s.d. from four mice. Similar results were obtained from three separate experiments. (c) After three oral immunizations with OVA plus cholera toxin, cells were isolated from the iLP and used in an ELISPOT assay to enumerate OVA-specific IgA AFCs. In some groups of mice, CD11b+ or CD11b− IgA+ cells were depleted by cell sorting before application of ELISPOT assay. Phosphorylcholine-specific IgA AFCs were measured. Graphs show data from individual mice, and bars indicate median. Statistical analyses were performed with Mann–Whitney’s U-test. (d) Mononuclear cells were isolated from the iLP of Peyer’s patch (PP)-normal (control Ab) and - (anti-IL-7Rα Ab) mice for analysis of IgA and CD11b expression by flow cytometry. Graphs show data from individual mice. Statistical analyses were performed with Mann–Whitney’s U-test. (e) Mononuclear cells were isolated from PPs for analysis of CD11b+ and CD11b− IgA+ cells by flow cytometry. Similar results were obtained from three separate experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: CD11b+ IgA+ cells require the lymphoid structure of Peyer’s patches.(a) Mice were treated with FTY720 every day for 5 days. The day after the final treatment, the proportions of CD11b+ and CD11b− IgA+ cells were measured by flow cytometry. Data are presented as means±s.d. from four mice. Similar results were obtained from three separate experiments. (b) Proportions of CD11b+and CD11b− IgA+ cells in the iLP of WT and TCRβδ KO mice were measured by flow cytometry. Data are presented as means±s.d. from four mice. Similar results were obtained from three separate experiments. (c) After three oral immunizations with OVA plus cholera toxin, cells were isolated from the iLP and used in an ELISPOT assay to enumerate OVA-specific IgA AFCs. In some groups of mice, CD11b+ or CD11b− IgA+ cells were depleted by cell sorting before application of ELISPOT assay. Phosphorylcholine-specific IgA AFCs were measured. Graphs show data from individual mice, and bars indicate median. Statistical analyses were performed with Mann–Whitney’s U-test. (d) Mononuclear cells were isolated from the iLP of Peyer’s patch (PP)-normal (control Ab) and - (anti-IL-7Rα Ab) mice for analysis of IgA and CD11b expression by flow cytometry. Graphs show data from individual mice. Statistical analyses were performed with Mann–Whitney’s U-test. (e) Mononuclear cells were isolated from PPs for analysis of CD11b+ and CD11b− IgA+ cells by flow cytometry. Similar results were obtained from three separate experiments.
Mentions: CD11b+ IgA+ PCs expressed CD18 (Supplementary Fig. S4), which associates with CD11b and acts as a ligand for intercellular adhesion molecule-1 (ICAM-1)24. As ICAM-1 is an endothelial adhesion molecule that regulates cell trafficking2425, we considered that CD11b+ IgA+ PCs were recent emigrants from IgA-inductive tissues (for example, PPs and PerC) and had migrated into the iLP. To test this possibility, we employed FTY720 to inhibit the trafficking of IgA-committed B cells from PPs and PerC into the iLP. As we previously reported1113, FTY720 treatment reduced the numbers of intestinal IgA+ PCs, but the effect was not specific to CD11b+ IgA+ PCs (Fig. 3a). These data suggested that CD11b+ IgA+ PCs were not recent emigrants from IgA inductive tissues (for example, PPs and PerC).

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