Retinoic acid determines the precise tissue tropism of inflammatory Th17 cells in the intestine - PubMed (original) (raw)

Comparative Study

. 2010 May 15;184(10):5519-26.

doi: 10.4049/jimmunol.0903942. Epub 2010 Apr 16.

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Comparative Study

Retinoic acid determines the precise tissue tropism of inflammatory Th17 cells in the intestine

Chuanwu Wang et al. J Immunol. 2010.

Abstract

Th17 cells are major effector T cells in the intestine, but the regulation of their tissue tropism within the gut is poorly understood. We investigated the roles of vitamin A and retinoic acid in generation of inflammatory Th17 cells with distinct tissue tropisms within the intestine. We found that Th17 cells with distinct tissue tropisms and pathogenic activities are generated depending on the available concentration of retinoic acid (RA). In contrast to the widespread perception that RA would suppress the generation of Th17 cells, we provide evidence that RA is actually required for generation of Th17 cells with specific tissue tropisms within the gut. Th17 cells induced at suboptimal serum concentrations of RA migrated and induced moderate inflammation mainly in the large intestine, whereas the Th17 cells induced with optimal levels of exogenous RA (approximately 10 nM) migrated to the small intestine and induced more severe inflammation. The Th17 cells, induced in the presence or absence of RA, differentially expressed the trafficking receptors CCR9 and alpha4beta7. CCR9 is required for Th17 cell migration to the small intestine, whereas alpha4beta7 is required for the migration of Th17 cells throughout the whole intestine. Our results identified RA as a major signal that regulates the generation of gut Th17 cells with distinct capacities in migration and inflammatory activities. The results indicate also that specific gut tropism of Th17 cells is determined by the combination of trafficking receptors regulated by the RA signal.

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Figures

Figure 1

Figure 1. Gut homing CCR9+α4β7+ Th17 cells are induced in the presence of physiological concentrations of RA

(A) Naïve T cells were cultured in a Th17 cell induction condition for 7 days at indicated concentrations of RA. (B) Expression of gut homing receptors (CCR9 and α4β7) by Th17 cells was examined. (C) The chemotactic ability of RA Th17 cells and control Th17 cells to CCL25 and CCL19. (D) Twenty hour short-term homing capacity of RA Th17 cells and control Th17 cells was compared in C57BL/6 mice. The Th17 cells were injected i.v. Homing index of RA Th17 cells is shown as % of control Th17 cells. *A significant increase in migration of RA Th17 cells over control Th17 cells. (E) Migration of RA Th17 cells is shown as % distribution among the indicated organs. *Significant differences from control Th17 cells. (F) In situ visualization of the RA Th17 cells and control Th17 cells migrated into indicated organs. All experiments were performed at least 3 times and combined (A-E) or representative data (F) are shown. Averages and SEM are shown in the combined data.

Figure 2

Figure 2. Th17 cells are decreased specifically in the small intestine of vitamin A-deficient animals

The frequencies of Th17 cells in various organs of vitamin A-sufficient and deficient AKR/J mice were determined. Representative (A) and combined (B) data of 3 independent experiments are shown. *Significant differences between RA and control Th17 cells.

Figure 3

Figure 3. RA Th17 cells use Itgβ7 to migrate to the whole intestine including the lamina propria and gut-associated lymphoid tissues

(A) Expression of CCR9 and α4β7 by wild type and Itgβ7 (−/−) RA Th17 cells. (B) The Th17 cells were injected i.v. and the migration of Th17 cells to the indicated organs were determined 20 h post cell-injection. (C) The localization of the injected Th17 cells in the indicated tissues was determined with a confocal microscope. The experiments were performed 3 times, and combined data (B) or representative data (C) are shown. *Significant changes.

Figure 4

Figure 4. RA Th17 cells use CCR9 to migrate to the small intestinal lamina propria

(A) Expression of CCR9 and α4β7 by wild type and CCR9 (−/−) RA Th17 cells. (B) The Th17 cells were injected i.v. and the short-term (20 h) migration of Th17 cells was determined. (C) The localization of the Th17 cells was determined with confocal microscopy. Combined data (B) or representative data (C) of 3 independent experiments are shown. *Significant changes.

Figure 5

Figure 5. The inflammatory activities of RA Th17 cells and control Th17 cells

RA Th17 cells and control Th17 cells were separately injected i.p. into Rag1-deficient mice. (A) Relative weight change due to intestinal inflammation. (B) H&E staining of the intestinal tissues (200 × original magnification). (C) Inflammation scores. Data obtained from 10–11 mice are shown. Significant differences from the no T cell group (*) or control Th17 cell group (**).

Figure 6

Figure 6. Roles of CCR9 and Itgβ7 for the inflammatory activity of RA Th17 cells

RA Th17 cells that are sufficient or deficient in expression of CCR9 or Itgβ7 were separately injected i.p. into Rag1-deficient mice to induce inflammation. (A) Weight change due to intestinal inflammation (n=10–11). (B) H&E staining of the intestinal tissues (200 × original magnification). (C) Histological scores (n=10–11). Significant differences from the wild type RA Th17 cell group (*).

Figure 7

Figure 7. Roles of CCR9 and Itgβ7 in long term population of Th17 cells and effector T cell balance in the intestine

RA Th17 cells that are sufficient or deficient in expression of CCR9 or Itgβ7 were injected i.p. into Rag1-deficient mice, and absolute numbers of Th1 and Th17 cells in the spleen, small intestine, and large intestine were determined ~30 days later. Significant differences from the wild type RA Th17 cell group (*). Absolute numbers of the T cells per organ detected by the method are shown. Combined data with averages and SEM are shown (n=10–12/group).

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References

    1. Ivanov, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126:1121–1133. - PubMed
    1. Wang C, Kang SG, Lee J, Sun Z, Kim CH. The roles of CCR6 in migration of Th17 cells and regulation of effector T-cell balance in the gut. Mucosal immunology. 2009;2:173–183. - PMC - PubMed
    1. Zaph C, Du Y, Saenz SA, Nair MG, Perrigoue JG, Taylor BC, Troy AE, Kobuley DE, Kastelein RA, Cua DJ, Yu Y, Artis D. Commensal-dependent expression of IL-25 regulates the IL-23-IL-17 axis in the intestine. The Journal of experimental medicine. 2008;205:2191–2198. - PMC - PubMed
    1. Ivanov, Frutos Rde L, Manel N, Yoshinaga K, Rifkin DB, Sartor RB, Finlay BB, Littman DR. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe. 2008;4:337–349. - PMC - PubMed
    1. Hung LY, Velichko S, Huang F, Thai P, Wu R. Regulation of airway innate and adaptive immune responses: the IL-17 paradigm. Crit Rev Immunol. 2008;28:269–279. - PubMed

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