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.
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Newberry, R.D. & Lorenz, R.G. Organizing a mucosal defense. Immunol. Rev. 206, 6–21 (2005).
Randall, T.D., Carragher, D.M. & Rangel-Moreno, J. Development of secondary lymphoid organs. Annu. Rev. Immunol. 26, 627–650 (2008).
Taylor, R.T. & Williams, I.R. Lymphoid organogenesis in the intestine. Immunol. Res. 33, 167–181 (2005).
Lorenz, R.G., Chaplin, D.D., McDonald, K.G., McDonough, J.S. & Newberry, R.D. Isolated lymphoid follicle formation is inducible and dependent upon lymphotoxin-sufficient B lymphocytes, lymphotoxin β receptor, and TNF receptor I function. J. Immunol. 170, 5475–5482 (2003).
Dohi, T. et al. Hapten-induced colitis is associated with colonic patch hypertrophy and T helper cell 2-type responses. J. Exp. Med. 189, 1169–1180 (1999).
Dohi, T. et al. Elimination of colonic patches with lymphotoxin β receptor-Ig prevents Th2 cell-type colitis. J. Immunol. 167, 2781–2790 (2001).
Lee, A.Y. et al. Dendritic cells in colonic patches and iliac lymph nodes are essential in mucosal IgA induction following intrarectal administration via CCR7 interaction. Eur. J. Immunol. 38, 1127–1137 (2008).
Kanamori, Y. et al. Identification of novel lymphoid tissues in murine intestinal mucosa where clusters of c-kit+ IL-7R+ Thy1+ lympho-hemopoietic progenitors develop. J. Exp. Med. 184, 1449–1459 (1996).
Eberl, G. et al. An essential function for the nuclear receptor RORγ(t) in the generation of fetal lymphoid tissue inducer cells. Nat. Immunol. 5, 64–73 (2004).
Eberl, G. & Littman, D.R. Thymic origin of intestinal αβ T cells revealed by fate mapping of RORγt+ cells. Science 305, 248–251 (2004).
Colonna, M. Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity. Immunity 31, 15–23 (2009).
Neill, D.R. et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367–1370 (2010).
Saenz, S.A. et al. IL25 elicits a multipotent progenitor cell population that promotes TH2 cytokine responses. Nature 464, 1362–1366 (2010).
Moro, K. et al. Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature 463, 540–544 (2010).
Hamada, H. et al. Identification of multiple isolated lymphoid follicles on the antimesenteric wall of the mouse small intestine. J. Immunol. 168, 57–64 (2002).
Bouskra, D. et al. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456, 507–510 (2008).
Drayton, D.L., Liao, S., Mounzer, R.H. & Ruddle, N.H. Lymphoid organ development: from ontogeny to neogenesis. Nat. Immunol. 7, 344–353 (2006).
Lügering, A. & Kucharzik, T. Induction of intestinal lymphoid tissue: the role of cryptopatches. Ann. NY Acad. Sci. 1072, 210–217 (2006).
Yokota, Y. et al. Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2. Nature 397, 702–706 (1999).
Taylor, R.T., Lugering, A., Newell, K.A. & Williams, I.R. Intestinal cryptopatch formation in mice requires lymphotoxin alpha and the lymphotoxin β receptor. J. Immunol. 173, 7183–7189 (2004).
Tsuji, M. et al. Requirement for lymphoid tissue-inducer cells in isolated follicle formation and T cell-independent immunoglobulin A generation in the gut. Immunity 29, 261–271 (2008).
Gommerman, J.L. & Browning, J.L. Lymphotoxin/light, lymphoid microenvironments and autoimmune disease. Nat. Rev. Immunol. 3, 642–655 (2003).
Ware, C.F. Network communications: lymphotoxins, LIGHT, and TNF. Annu. Rev. Immunol. 23, 787–819 (2005).
Wang, Y. et al. Lymphotoxin β receptor signaling in intestinal epithelial cells orchestrates innate immune responses against mucosal bacterial infection. Immunity 32, 403–413 (2010).
Cella, M. et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 457, 722–725 (2009).
Satoh-Takayama, N. et al. Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity 29, 958–970 (2008).
Sanos, S.L. et al. RORγt and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nat. Immunol. 10, 83–91 (2009).
Luci, C. et al. Influence of the transcription factor RORγt on the development of NKp46+ cell populations in gut and skin. Nat. Immunol. 10, 75–82 (2009).
Takatori, H. et al. Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J. Exp. Med. 206, 35–41 (2009).
Sonnenberg, G.F., Monticelli, L.A., Elloso, M.M., Fouser, L.A. & Artis, D. CD4+ lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity 34, 122–134 (2011).
Ouyang, W., Rutz, S., Crellin, N.K., Valdez, P.A. & Hymowitz, S.G. Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu. Rev. Immunol. 29, 71–109 (2011).
Ouyang, W., Kolls, J.K. & Zheng, Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28, 454–467 (2008).
Wolk, K. et al. IL-22 increases the innate immunity of tissues. Immunity 21, 241–254 (2004).
Sa, S.M. et al. The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis. J. Immunol. 178, 2229–2240 (2007).
Zheng, Y. et al. Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445, 648–651 (2007).
Zheng, Y. et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat. Med. 14, 282–289 (2008).
Mundy, R., MacDonald, T.T., Dougan, G., Frankel, G. & Wiles, S. Citrobacter rodentium of mice and man. Cell Microbiol. 7, 1697–1706 (2005).
McDonald, K.G., McDonough, J.S. & Newberry, R.D. Adaptive immune responses are dispensable for isolated lymphoid follicle formation: antigen-naive, lymphotoxin-sufficient B lymphocytes drive the formation of mature isolated lymphoid follicles. J. Immunol. 174, 5720–5728 (2005).
Spahn, T.W. et al. The lymphotoxin-beta receptor is critical for control of murine Citrobacter rodentium-induced colitis. Gastroenterology 127, 1463–1473 (2004).
Alimzhanov, M.B. et al. Abnormal development of secondary lymphoid tissues in lymphotoxin β-deficient mice. Proc. Natl. Acad. Sci. USA 94, 9302–9307 (1997).
Tamada, K. et al. Cutting edge: selective impairment of CD8+ T cell function in mice lacking the TNF superfamily member LIGHT. J. Immunol. 168, 4832–4835 (2002).
Marchesi, F. et al. CXCL13 expression in the gut promotes accumulation of IL-22-producing lymphoid tissue-inducer cells, and formation of isolated lymphoid follicles. Mucosal Immunol. 2, 486–494 (2009).
Zenewicz, L.A. et al. Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity 27, 647–659 (2007).
Sugimoto, K. et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J. Clin. Invest. 118, 534–544 (2008).
Pickert, G. et al. STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J. Exp. Med. 206, 1465–1472 (2009).
Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V.K. IL-17 and Th17 cells. Annu. Rev. Immunol. 27, 485–517 (2009).
Aloisi, F. & Pujol-Borrell, R. Lymphoid neogenesis in chronic inflammatory diseases. Nat. Rev. Immunol. 6, 205–217 (2006).
Ozaki, K. et al. A critical role for IL-21 in regulating immunoglobulin production. Science 298, 1630–1634 (2002).
Hsu, H.C. et al. Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat. Immunol. 9, 166–175 (2008).
Wong, K. et al. Phosphatidylserine receptor Tim-4 is essential for the maintenance of the homeostatic state of resident peritoneal macrophages. Proc. Natl. Acad. Sci. (USA) 107, 8712–8717 (2010).
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.
All authors are employees of Genentech.
About this article
Cite this article
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
The Journal of Immunology (2021)
British Journal of Pharmacology (2021)
International Immunopharmacology (2021)
Indole-3-Carbinol Inhibits Citrobacter rodentium Infection through Multiple Pathways Including Reduction of Bacterial Adhesion and Enhancement of Cytotoxic T Cell Activity