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The molecular basis and cellular effects of distinct CD103 expression on CD4 and CD8 T cells

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Abstract

Integrin CD103 mediates the adhesion and tissue retention of T cells by binding to E-cadherin which is abundant on epithelial cells. Notably, CD103 is highly expressed on CD8 T cells but conspicuously absent on most CD4 T cells. The mechanism controlling such lineage-specific expression of CD103 remains unclear. Using a series of genetically engineered mouse models, here, we demonstrate that the regulatory mechanism of CD103 expression is distinct between CD4 and CD8 T cells, and that the transcription factor Runx3 plays an important but not an essential role in this process. We further found that the availability of integrin β7 which heterodimerizes with CD103 was necessary but also constrained the surface expression of CD103. Notably, the forced surface expression of CD103 did not significantly alter the thymic development of conventional T cells but severely impaired the generation of MHC-II-restricted TCR transgenic T cells, revealing previously unappreciated aspects of CD103 in the selection and maturation of CD4 T cells. Unlike its effect on CD4 T cell development, however, CD103 overexpression did not significantly affect CD4 T cells in peripheral tissues. Moreover, the frequency and number of CD4 T cells in the small intestine epithelium did not increase even though E-cadherin is highly expressed in this tissue. Collectively, these results suggest that most mature CD4 T cells are refractory to the effects of CD103 expression, and that they presumably utilize CD103-independent pathways to control their tissue retention and residency.

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Acknowledgements

We thank the General Surgery Department and Residency Program, Guthrie Robert Packer Hospital, for support in allowing Hilary R. Keller an interruption in her residency training to join the National Institutes of Health Cancer Research Training Award fellowship program.

Funding

This study has been supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research, and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI18C0479).

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Author notes

  1. Davinna L. Ligons and Can Li have equally contributed to this work.

Authors and Affiliations

  1. Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA

    Hilary R. Keller, Davinna L. Ligons, Can Li, SuJin Hwang, Megan A. Luckey, Praveen Prakhar, Nurcin Liman, Assiatu Crossman, Vanja Lazarevic & Jung-Hyun Park

  2. Department of Surgery, Guthrie Robert Packer Hospital, Sayre, PA, 18840, USA

    Hilary R. Keller

  3. Department of Medical Nutrition-AgeTech-Service Convergence Major, Graduate School of East-West Medical Science, Kyung Hee University, Yongin-si, Gyeonggi-do, 17104, South Korea

    Yoo Kyoung Park

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  1. Hilary R. Keller
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Contributions

HRK, DLL, and CL designed and performed the experiments, analyzed the data, and contributed to the writing of the manuscript. SH, MAL, PP, NL, AC, and VL performed the experiments, analyzed the data, and commented on the manuscript. YKP and JHP conceived the project, analyzed the data, and wrote the manuscript.

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Correspondence to Yoo Kyoung Park or Jung-Hyun Park.

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Keller, H.R., Ligons, D.L., Li, C. et al. The molecular basis and cellular effects of distinct CD103 expression on CD4 and CD8 T cells. Cell. Mol. Life Sci. 78, 5789–5805 (2021). https://doi.org/10.1007/s00018-021-03877-9

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