Editors' ChoiceImmunology

An Arrestin Immune Response

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Science's STKE  31 Jul 2007:
Vol. 2007, Issue 397, pp. tw268
DOI: 10.1126/stke.3972007tw268

Our survival depends on the elimination of pathogens by the immune system. If not kept in check, however, the immune system can become self-destructive, and dysregulation of the adaptive immune response—for instance, failure to eliminate effector T cells after a pathogen has been cleared—is associated with the development of autoimmune disorders (see Frederick and Miller). Shi et al. found that mice lacking Arrb1, which encodes β-arrestin-1 (a scaffolding protein identified in terms of its cytoplasmic role in G protein-coupled receptor signaling but since discovered to act in the nucleus as well), had fewer peripheral CD4+ T cells than did wild-type mice. Naive and activated CD4+ T cells from Arrb1–/– mice were more likely to undergo apoptosis than those from wild-type mice, whereas activated CD4+ T cells from Arrb1-transgenic mice (Arrb1tg mice) were less likely to do so. Several days after an immunological challenge, Arrb1–/– mice had a smaller population of responding CD4+ T cells than did wild-type mice, whereas Arrb1tg mice had a larger population. Arrb1 knockdown led to a decrease in transcription of the gene encoding the antiapoptotic protein Bcl-2. After CD4+ T cell activation, Bcl-2 expression tracked that of Arrb1; such dynamic changes in Bcl-2 expression were absent in Arrb1–/– cells. Further analysis indicated that β-arrestin-1 stimulated Bcl-2 expression through acetylation of histone H4 at the Bcl-2 promoter. Intriguingly, Arrb1–/– mice were less susceptible to experimental autoimmune encephalomyelitis than were wild-type mice, whereas Arrb1tg mice were more susceptible, and CD4+ T cells from people with multiple sclerosis showed increased expression of ARRB1 and BCL2. Moreover, β-arrestin-1 knockdown in CD4+ T cells directed against myelin basic protein led to a decrease in Bcl-2 and an increased susceptibility to apoptosis. Thus, the authors conclude that β-arrestin-1 plays a key role in CD4+ T cell homeostasis by regulating the expression of Bcl-2.

Y. Shi, Y. Feng, J. Kang, C. Liu, Z. Li, D. Li, W. Cao, J. Qiu, Z. Guo, E. Bi, L. Zang, C. Lu, J. Z. Zhang, G. Pei, Critical regulation of CD4+ T cell survival and autoimmunity by β-arrestin 1. Nat. Immunol. 8, 817-824 (2007). [PubMed]

T. J. Frederick, S. D. Miller, Arresting autoimmunity by blocking β-arrestin 1. Nat. Immunol. 8, 791-792 (2007). [PubMed]

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