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Critical regulation of CD4+ T cell survival and autoimmunity by β-arrestin 1

Nature Immunology volume 8, pages 817–824 (2007)Cite this article

Abstract

CD4+ T cells are important in adaptive immunity, but their dysregulation can cause autoimmunity. Here we demonstrate that the multifunctional adaptor protein β-arrestin 1 positively regulated naive and activated CD4+ T cell survival. We found enhanced expression of the proto-oncogene Bcl2 through β-arrestin 1–dependent regulation of acetylation of histone H4 at the Bcl2 promoter. Mice deficient in the gene encoding β-arrestin 1 (Arrb1) were much more resistant to experimental autoimmune encephalomyelitis, whereas overexpression of Arrb1 increased susceptibility to this disease. CD4+ T cells from patients with multiple sclerosis had much higher Arrb1 expression, and 'knockdown' of Arrb1 by RNA-mediated interference in those cells increased apoptosis induced by cytokine withdrawal. Our data demonstrate that β-arrestin 1 is critical for CD4+ T cell survival and is a factor in susceptibility to autoimmunity.

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Figure 1: Involvement of β-arrestin 1 in the homeostasis and survival of CD4+ T cells.
Figure 2: Promotion of Bcl2 expression by β-arrestin 1 in CD4+ T cells.
Figure 3: Promotion of acetylation of histone H4 at the Bcl2 locus by β-arrestin 1.
Figure 4: Critical involvement of β-arrestin 1 in EAE.
Figure 5: Critical involvement of β-arrestin 1 in the pathogenesis of multiple sclerosis.

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Acknowledgements

We thank R.J. Lefkowitz (Duke University Medical Center) for rabbit polyclonal anti-β-arrestin (A1CT) and for Arrb1−/− and Arrb2−/− mice; Y. Shi, J. Cai and X. Liu for discussions; and S. Xin, Y. Li, G. Ding, P. Wu and S. Chen for technical assistance. Supported by the Ministry of Science and Technology (2003CB515405 and 2005CB522406), the National Natural Science Foundation of China (30021003, 30623003, 30625014, 30400230, 30430650 and 30571731), the Shanghai Municipal Commission for Science and Technology (06ZR14098, 04JC14040, 04DZ14902 and PJ200500330), the Shanghai Municipal Health Bureau (LJ06046), the Shanghai Leading Academic Discipline Project (T206) and the Chinese Academy of Sciences (KSCX2-YW-R-56).

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Authors and Affiliations

  1. Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China

    Yufeng Shi, Jiuhong Kang, Chang Liu, Enguang Bi, Lei Zang & Gang Pei

  2. Joint Immunology Laboratory of Institute of Health Sciences and Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200025, China

    Yan Feng, Wei Cao, Ju Qiu & Jingwu Z Zhang

  3. Institute of Neurology, Huashan Hospital, Shanghai Medical College of Fudan University, Shanghai, 200040, China

    Zhenxin Li & Chuanzhen Lu

  4. Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China

    Dangsheng Li

  5. Department of Neurology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200025, China

    Zhengliang Guo & Jingwu Z Zhang

  6. E-Institutes of Shanghai Universities, Shanghai, 200240, China

    Jingwu Z Zhang

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Contributions

Y.S. designed and did the experiments and prepared the manuscript; Y.F. and J.K. designed and did the experiments and analyzed the data; C.L. assisted with cell purification, activation and culture; Z.L., Z.G. and C.L. provided the blood samples from patients with multiple sclerosis; D.L. prepared the manuscript; W.C. and J.Q. assisted with the induction of EAE; E.B. and L.Z. assisted with cell purification, activation and culture; and J.Z.Z. and G.P. supervised all studies and the preparation of the manuscript.

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Correspondence to Jingwu Z Zhang or Gang Pei.

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Shi, Y., Feng, Y., Kang, J. et al. Critical regulation of CD4+ T cell survival and autoimmunity by β-arrestin 1. Nat Immunol 8, 817–824 (2007). https://doi.org/10.1038/ni1489

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