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

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. Access through your institution Buy or subscribe This is a preview of

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February 2022 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

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IL-10. _J. Immunol._ 173, 4479–4491 (2004). Article  CAS  Google Scholar  Download references 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.). AUTHOR

INFORMATION AUTHORS AND AFFILIATIONS * 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 * Department of Immunology and Microbiology, Weill Medical College of Cornell University, New York,

10021, New York, USA Meimei Shan & Aihao Ding * Graduate Program of Immunology and Microbial Pathogenesis, Weill Medical College of Cornell University, New York, 10021, New York, USA

Aihao Ding & Andrea Cerutti Authors * Weifeng Xu View author publications You can also search for this author inPubMed Google Scholar * Bing He View author publications You can also

search for this author inPubMed Google Scholar * April Chiu View author publications You can also search for this author inPubMed Google Scholar * Amy Chadburn View author publications You

can also search for this author inPubMed Google Scholar * Meimei Shan View author publications You can also search for this author inPubMed Google Scholar * Malwina Buldys View author

publications You can also search for this author inPubMed Google Scholar * Aihao Ding View author publications You can also search for this author inPubMed Google Scholar * Daniel M Knowles

View author publications You can also search for this author inPubMed Google Scholar * Paul A Santini View author publications You can also search for this author inPubMed Google Scholar *

Andrea Cerutti View author publications You can also search for this author inPubMed Google Scholar 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. CORRESPONDING AUTHOR Correspondence to Andrea Cerutti. ETHICS DECLARATIONS COMPETING INTERESTS The

authors declare no competing financial interests. 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) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS

ARTICLE 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 Download citation * Received: 12 September 2006 * Accepted: 21 December 2006 * Published: 28 January 2007 * Issue Date: March 2007 * DOI:

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