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Regulation of T cell development by the deubiquitinating enzyme CYLD

Nature Immunology volume 7, pages 411–417 (2006)Cite this article

Abstract

T cell receptor signaling is essential for the generation and maturation of T lymphocyte precursors. Here we identify the deubiquitinating enzyme CYLD as a positive regulator of proximal T cell receptor signaling in thymocytes. CYLD physically interacted with active Lck and promoted recruitment of active Lck to its substrate, Zap70. CYLD also removed both Lys 48– and Lys 63–linked polyubiquitin chains from Lck. Because of a cell-autonomous defect in T cell development, CYLD-deficient mice had substantially fewer mature CD4+ and CD8+ single-positive thymocytes and peripheral T cells.

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Figure 1: CYLD in innate immune receptor signaling.
Figure 2: T cell development in Cyld−/− mice.
Figure 3: TCR signaling in Cyld −/− thymocytes.
Figure 4: CYLD-mediated Lck-Zap70 association.
Figure 5: CYLD-mediated deubiquitination of Lck.

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Acknowledgements

We thank T. Saunders and E. Hughes of the University of Michigan Transgenic Core (Ann Arbor, Michigan) for the production of CYLD chimera mice; N. Sheaffer, A. Stanley and J. Bednarczyk of the Pennsylvania State College of Medicine Core facilities (Hershey, Pennsylvania) for assistance with flow cytometry, oligonucleotide synthesis and DNA sequencing; A. Nagy, R. Nagy and W. Abramow-Newerly of Mount Sinai Hospital (New York, New York) for the R1 embryonic stem cells; H. Band (Northwestern University, Chicago, Illinois), S. Lipkowitz (National Cancer Institute, Bethesda, Maryland) and Z. Chen (University of Texas Southwestern Medical Center, Dallas, Texas) for providing Lck, c-Cbl and ubiquitin expression vectors, respectively; and J. Lee for critical reading of the manuscript. Supported by National Institutes of Health (AI057555 to S.C.S. and M.Y.Z.; CA94922 to S.C.S.; AI056094 to C.C.N.; and C06 RR-15428-01 to the Pennsylvania State College of Medicine Animal Facility).

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  1. Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, 17033, Pennsylvania, USA

    William W Reiley, Minying Zhang, Wei Jin, Mandy Losiewicz, Keri B Donohue, Christopher C Norbury & Shao-Cong Sun

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Correspondence to Shao-Cong Sun.

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Supplementary information

Supplementary Fig. 1

Generation of Cyld−/− mice. (PDF 78 kb)

Supplementary Fig. 2

Surface phenotype of wild-type and Cyld−/− thymocytes. (PDF 90 kb)

Supplementary Fig. 3

Purity of isolated DP thymocytes. (PDF 101 kb)

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Reiley, W., Zhang, M., Jin, W. et al. Regulation of T cell development by the deubiquitinating enzyme CYLD. Nat Immunol 7, 411–417 (2006). https://doi.org/10.1038/ni1315

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