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Epithelial cells trigger frontline immunoglobulin class switching through a pathway regulated by the inhibitor SLPI

Nature Immunology volume 8, pages 294–303 (2007)Cite this article

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Abstract

Epithelial cells (ECs) transport class-switched immunoglobulin G (IgG) and IgA antibodies across mucous membranes. Whether ECs initiate class switching remains unknown. Here we found that ECs lining tonsillar crypts formed pockets populated by B cells expressing activation-induced cytidine deaminase (AID), an enzyme associated with ongoing class switching. ECs released B cell–activating AID-inducing factors after sensing microbial products through Toll-like receptors. The resulting class switching was amplified by thymic stromal lymphopoietin, an epithelial interleukin 7–like cytokine that enhanced the B cell 'licensing' function of dendritic cells, and was restrained by secretory leukocyte protease inhibitor, an epithelial homeostatic protein that inhibited AID induction in B cells. Thus, ECs may function as mucosal 'guardians' orchestrating frontline IgG and IgA class switching through a Toll-like receptor–inducible signaling program regulated by secretory leukocyte protease inhibitor.

NOTE: In the version of this article initially published online, the middle label above Figure 6c is incorrect. The correct label should be ‘BAFF’. The error has been corrected for all versions of the article.

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Figure 1: Tonsillar ECs express the AID-inducing ligand BAFF and form mucosal pockets infiltrated by AID-expressing B cells.
Figure 2: ECs release BAFF and IL-10 and induce AID expression as well as IgG and IgA class switching in B cells after sensing viral RNA.
Figure 3: ECs exposed to viral RNA induce class switching by activating B cells through BAFF.
Figure 4: Tonsillar ECs interact closely with BAFF-expressing DCs and upregulate the DC-stimulating cytokine TSLP in response to viral RNA.
Figure 5: TSLP amplifies EC-induced class switching by stimulating DCs to produce more BAFF.
Figure 6: Tonsillar ECs express SLPI and form intraepithelial pockets containing SLPI+ B cells.
Figure 7: SLPI negatively regulates class switching in B cells exposed to viral RNA, BAFF and IL-10.

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Change history

  • 08 February 2007

    In the version of this article initially published online, the middle label above Figure 6c is incorrect. The correct label should be ‘BAFF’. The error has been corrected for all versions of the article.

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Acknowledgements

We thank C. Nathan (Weill Medical College of Cornell University) and M. Rescigno (European Institute of Oncology) for reagents and discussions. Supported by the National Institutes of Health (AI057653 to A.C.; and T32 AI07621, supporting W.X.).

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, 10021, New York, USA

    Weifeng Xu, Bing He, April Chiu, Amy Chadburn, Malwina Buldys, Daniel M Knowles, Paul A Santini & Andrea Cerutti

  2. Department of Immunology and Microbiology, Weill Medical College of Cornell University, New York, 10021, New York, USA

    Meimei Shan & Aihao Ding

  3. Graduate Program of Immunology and Microbial Pathogenesis, Weill Medical College of Cornell University, New York, 10021, New York, USA

    Aihao Ding & Andrea Cerutti

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Contributions

W.X. designed and did research and analyzed data; B.H., M.S. and M.D. did research; A. Chiu provided tissue samples and discussed data; A. Chadburn and D.M.K. provided tissue samples; A.D. provided reagents, discussed data and edited the paper; P.A.S. analyzed and discussed data; and A. Cerutti designed research, analyzed data and wrote the paper.

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Correspondence to Andrea Cerutti.

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Supplementary information

Supplementary Fig. 1

Primary oral ECs lack contaminating DCs and express BAFF. (PDF 185 kb)

Supplementary Fig. 2

Intestinal and epidermal ECs express BAFF and TLR3. (PDF 195 kb)

Supplementary Fig. 3

Intestinal and epidermal ECs express TLR9. (PDF 153 kb)

Supplementary Fig. 4

B cells up-regulate TLR3 expression upon exposure to viral RNA and BAFF. (PDF 194 kb)

Supplementary Fig. 5

ECs stimulate IgD+ B cells to undergo IgG and IgA CSR. (PDF 120 kb)

Supplementary Fig. 6

ECs stimulate IgD+ B cells to produce broadly reactive IgG and IgM antibodies. (PDF 135 kb)

Supplementary Fig. 7

Phenotype of myeloid DCs. (PDF 126 kb)

Supplementary Fig. 8

Tonsillar ECs and intraepithelial B cells contain SLPI. (PDF 136 kb)

Supplementary Fig. 9

SLPI inhibits IgG and IgA production in IgD+ B cells exposed to CD40L, IL-4 and IL-10. (PDF 65 kb)

Supplementary Fig. 10

ECs induce frontline IgG and IgA class switching through a TLR-inducible SLPI-regulated epithelial pathway. (PDF 108 kb)

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Xu, W., He, B., Chiu, A. et al. Epithelial cells trigger frontline immunoglobulin class switching through a pathway regulated by the inhibitor SLPI. Nat Immunol 8, 294–303 (2007). https://doi.org/10.1038/ni1434

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