Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Mar;50(3):404-417.
doi: 10.1002/eji.201948327. Epub 2019 Dec 1.

CCR9 signaling in dendritic cells drives the differentiation of Foxp3+ Tregs and suppresses the allergic IgE response in the gut

Manisha Pathak  1 , Priyanka Padghan  1 , Namrita Halder  1 , Shilpi  1 , Neeraja Kulkarni  1 , Sandip A Sonar  1 , Girdhari Lal  1
Affiliations
Free article

CCR9 signaling in dendritic cells drives the differentiation of Foxp3+ Tregs and suppresses the allergic IgE response in the gut

Manisha Pathak et al. Eur J Immunol. 2020 Mar.
Free article

Abstract

The chemokine receptor CCR9 and its only known ligand CCL25 play an important role in gut inflammation and autoimmune colitis. The function of CCR9-CCL25 in the migration of immune cells is well characterized. However, its role in the immune cell differentiation is mostly not known. Using dextran sodium sulfate (DSS)-induced gut inflammation model, we showed that CCR9+ dendritic cells (DCs) specifically CD11b- CD103+ DCs were significantly increased in the gut-associated lymphoid tissues (GALT) compared to control mice. These CCR9+ DCs express lower MHC II and CD86 molecules and had regulatory surface markers (FasL and latency-associated peptide, LAP) in the GALT. In the presence of CCL25, CCR9+ DCs promoted in vitro differentiation of Foxp3+ regulatory CD4+ T cells (Tregs). CCL25-induced differentiation of Tregs was due to intrinsic signaling in the DCs but not through CD4+ T cells, which was driven by the production of thymic stromal lymphopoietin (TSLP) and not IL-10. Furthermore, adoptive transfer of CCR9+ DCs in C57BL/6 mice promoted Tregs but reduced the Th17 cells in the GALT, and also suppressed the OVA-specific gut-allergic response. Our results suggest CCR9+ DCs have a regulatory function and may provide a new cellular therapeutic strategy to control gut inflammation and allergic immune reaction.

Keywords: CCL25; CCR9; Foxp3; dendritic cells; mucosal tolerance.

PubMed Disclaimer

References

    1. Kulkarni, N., Pathak, M. and Lal, G., Role of chemokine receptors and intestinal epithelial cells in the mucosal inflammation and tolerance. J. Leukoc. Biol. 2017. 101: 377-394.
    1. Pabst, O., Ohl, L., Wendland, M., Wurbel, M. A., Kremmer, E., Malissen, B. and Forster, R., Chemokine receptor CCR9 contributes to the localization of plasma cells to the small intestine. J. Exp. Med. 2004. 199: 411-416.
    1. Bowman, E. P., Kuklin, N. A., Youngman, K. R., Lazarus, N. H., Kunkel, E. J., Pan, J., Greenberg, H. B. et al., The intestinal chemokine thymus-expressed chemokine (CCL25) attracts IgA antibody-secreting cells. J. Exp. Med. 2002. 195: 269-275.
    1. Cassani, B., Villablanca, E. J., Quintana, F. J., Love, P. E., Lacy-Hulbert, A., Blaner, W. S., Sparwasser, T. et al., Gut-tropic T cells that express integrin alpha4beta7 and CCR9 are required for induction of oral immune tolerance in mice. Gastroenterology 2011. 141: 2109-2118.
    1. Trivedi, P. J., Bruns, T., Ward, S., Mai, M., Schmidt, C., Hirschfield, G. M., Weston, C. J. and Adams, D. H., Intestinal CCL25 expression is increased in colitis and correlates with inflammatory activity. J. Autoimmun. 2016. 68: 98-104.

Publication types

LinkOut - more resources