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IL-22 bridges the lymphotoxin pathway with the maintenance of colonic lymphoid structures during infection with Citrobacter rodentium

Abstract

Colonic patches (CLPs) and isolated lymphoid follicles (ILFs) are two main lymphoid structures in the colon. Lymphoid tissue–inducer cells (LTi cells) are indispensable for the development of ILFs. LTi cells also produce interleukin 17 (IL-17) and IL-22, signature cytokines secreted by IL-17-producing helper T cells. Here we report that IL-22 acted downstream of the lymphotoxin pathway and regulated the organization and maintenance of mature CLPs and ILFs in the colon during infection with Citrobacter rodentium. Lymphotoxin (LTα1β2) regulated the production of IL-22 during infection with C. rodentium, but the lymphotoxin-like protein LIGHT did not. IL-22 signaling was sufficient to restore the organization of CLPs and ILFs and host defense against infection with C. rodentium in mice lacking lymphotoxin signals, which suggests that IL-22 connects the lymphotoxin pathway to mucosal epithelial defense mechanisms.

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Figure 1: Blockade of lymphotoxin signaling affects CLP and ILF structure in colons from mice infected with C. rodentium.
Figure 2: Blockade of the lymphotoxin pathway inhibits IL-22 expression in colons of mice infected with C. rodentium.
Figure 3: Exogenous IL-23 restores IL-22 induction and host defense during infection with C. rodentium when the lymphotoxin pathway is blocked.
Figure 4: Normal lymphoid structure development in IL-22-deficient mice.
Figure 5: IL-22 blockade disrupts the normal organization of CLPs and ILFs during infection with C. rodentium.
Figure 6: IL-22–Fc rescues mice treated with LTβR-Fc during infection with C. rodentium.
Figure 7: IL-22–Fc restores the structure of CLPs and ILFs in colons of mice treated LTβR-Fc during infection with C. rodentium.

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Acknowledgements

We thank J. Ding for generating all plasmids used; R. Alvarado for help with the collection of colons, enzyme-linked immunosorbent assays and RT-PCR analyses; J. Eastham-Anderson for help with imaging on the Ariol SL-50; D. Yan and J. Zhang for technical assistance with gavage; J. Zavala-Solorio for colon photographs; N. Ghilardi (Genentech) for the plasmid expressing IL-23; Y.-X. Fu and Y. Wang (University of Chicago) for LTβ- and LIGHT-deficient mice and analysis of those mice; and F. Martin and M. Balazs for suggestions and discussions.

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N.O., K.W. and P.A.V. did most of experiments and analyzed the data; Y.Z. contributed to Figure 2; L.D. analyzed the histological results in Figure 6g,h; N.K.C. contributed to Supplementary Figure 3; W.O. devised and planned the project; and W.O., N.O., K.W. and P.A.V. wrote the manuscript.

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Correspondence to Wenjun Ouyang.

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All authors are employees of Genentech.

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Ota, N., Wong, K., Valdez, P. et al. IL-22 bridges the lymphotoxin pathway with the maintenance of colonic lymphoid structures during infection with Citrobacter rodentium. Nat Immunol 12, 941–948 (2011). https://doi.org/10.1038/ni.2089

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