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Chemokine receptor CCR9 suppresses the differentiation of CD4+CD8αα+ intraepithelial T cells in the gut

Abstract

The chemokine receptor CCR9 equips T cells with the ability to respond to CCL25, a chemokine that is highly expressed in the thymus and the small intestine (SI). Notably, CCR9 is mostly expressed on CD8 but not on CD4 lineage T cells, thus imposing distinct tissue tropism on CD4 and CD8 T cells. The molecular basis and the consequences for such a dichotomy, however, have not been fully examined and explained. Here, we demonstrate that the forced expression of CCR9 interferes with the tissue trafficking and differentiation of CD4 T cells in SI intraepithelial tissues. While CCR9 overexpression did not alter CD4 T cell generation in the thymus, the forced expression of CCR9 was detrimental for the proper tissue distribution of CD4 T cells in the periphery, and strikingly also for their terminal differentiation in the gut epithelium. Specifically, the differentiation of SI epithelial CD4 T cells into immunoregulatory CD4+CD8αα+ T cells was impaired by overexpression of CCR9 and conversely increased by the genetic deletion of CCR9. Collectively, our results reveal a previously unappreciated role for CCR9 in the tissue homeostasis and effector function of CD4 T cells in the gut.

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Fig. 1: CCR9 downregulation is associated with CD4 lineage specification.
Fig. 2: Forced CCR9 expression does not interfere with CD4SP thymocyte development.
Fig. 3: Forced CCR9 expression skews peripheral tissue distribution of CD4 T cells.
Fig. 4: Characterization of SI IEL T cells in CCR9Tg mice.
Fig. 5: Forced expression of CCR9 is detrimental for the differentiation of DP IEL T cells.
Fig. 6: Tissue-specific mapping of CCR9-mediated differentiation of DP IEL T cells.

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Acknowledgements

We thank Drs. Paul Love (NICHD) and Yousuke Takahama (NCI) for critical review of this manuscript. This study has been supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research. This project has been also funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261201500003I. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

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C.L. designed and performed experiments, analyzed data, and contributed to the writing of the manuscript. H.K., P.P., S.L., A.C., D.L., M.L., and P.A. performed experiments, analyzed data, and commented on the manuscript. R.G. provided expertise and reviewed, commented on the manuscript. J.P. conceived the project, analyzed the data, and wrote the manuscript.

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Correspondence to Jung-Hyun Park.

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Li, C., Kim, H.K., Prakhar, P. et al. Chemokine receptor CCR9 suppresses the differentiation of CD4+CD8αα+ intraepithelial T cells in the gut. Mucosal Immunol 15, 882–895 (2022). https://doi.org/10.1038/s41385-022-00540-9

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