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The SKI proto-oncogene restrains the resident CD103+CD8+ T cell response in viral clearance

Cellular & Molecular Immunology volume 18, pages 2410–2421 (2021)Cite this article

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Abstract

Acute viral infection causes illness and death. In addition, an infection often results in increased susceptibility to a secondary infection, but the mechanisms behind this susceptibility are poorly understood. Since its initial identification as a marker for resident memory CD8+ T cells in barrier tissues, the function and regulation of CD103 integrin (encoded by ITGAE gene) have been extensively investigated. Nonetheless, the function and regulation of the resident CD103+CD8+ T cell response to acute viral infection remain unclear. Although TGFβ signaling is essential for CD103 expression, the precise molecular mechanism behind this regulation is elusive. Here, we reveal a TGFβ–SKI–Smad4 pathway that critically and specifically directs resident CD103+CD8+ T cell generation for protective immunity against primary and secondary viral infection. We found that resident CD103+CD8+ T cells are abundant in both lymphoid and nonlymphoid tissues from uninfected mice. CD103 acts as a costimulation signal to produce an optimal antigenic CD8+ T cell response to acute viral infection. There is a reduction in resident CD103+CD8+ T cells following primary infection that results in increased susceptibility of the host to secondary infection. Intriguingly, CD103 expression inversely and specifically correlates with SKI proto-oncogene (SKI) expression but not R-Smad2/3 activation. Ectopic expression of SKI restricts CD103 expression in CD8+ T cells in vitro and in vivo to hamper viral clearance. Mechanistically, SKI is recruited to the Itgae loci to directly suppress CD103 transcription by regulating histone acetylation in a Smad4-dependent manner. Our study therefore reveals that resident CD103+CD8+ T cells dictate protective immunity during primary and secondary infection. Interfering with SKI function may amplify the resident CD103+CD8+ T cell response to promote protective immunity.

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Data availability

ChIP-seq data are deposited in the GEO database under ID code GSE135533.

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Acknowledgements

We thank E. Robertson and E. Bikoff for providing Smad4fl/fl mice, H. Moses for providing TgfbrIIfl/fl mice, and the NIH tetramer core facility at Emory University for providing the tetramers. This work was supported by NIH funding (R01AI143894; R01AI138337) for J.K.W.; the NIH (AI123193); the National Multiple Sclerosis Society (RG-1802-30483); and the Yang Family Biomedical Scholars Award for Y.Y.W.

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  1. These authors contributed equally: Bing Wu, Ge Zhang

Authors and Affiliations

  1. Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Bing Wu, Ge Zhang, Zengli Guo, Gang Wang, Jason K. Whitmire & Yisong Y. Wan

  2. Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Bing Wu, Ge Zhang, Zengli Guo, Gang Wang, Jason K. Whitmire & Yisong Y. Wan

  3. Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, Liaoning, 116044, China

    Ge Zhang

  4. Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China

    Gang Wang & Junnian Zheng

  5. Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, Chapel Hill, NC, 27709, USA

    Xiaojiang Xu & Jian-liang Li

  6. Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Jason K. Whitmire

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Contributions

B.W. and G.Z. contributed equally to the design and implementation of the cellular, molecular, biochemical, and animal experiments; B.W. contributed to the writing of the manuscript; Z.G., G.W., and J. Z. contributed to the generation and characterization of SKI-KI mice; J.L. and X.X. contributed to the bioinformatic analysis of ChIP data; J.K.W. contributed to the LCMV infection model; and Y.Y.W. conceived the project, designed the experiments, and wrote the manuscript.

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Correspondence to Junnian Zheng or Yisong Y. Wan.

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Wu, B., Zhang, G., Guo, Z. et al. The SKI proto-oncogene restrains the resident CD103+CD8+ T cell response in viral clearance. Cell Mol Immunol 18, 2410–2421 (2021). https://doi.org/10.1038/s41423-020-0495-7

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