arresting autoimmunity by blocking β-arrestin 1
TRANSCRIPT
Arresting autoimmunity by blocking β-arrestin 1Terra J Frederick & Stephen D Miller
The regulation of T cell survival and apoptosis contributes to the pathogenesis of autoimmune disease. A new study shows that the transcriptional regulator β-arrestin 1 enhances antiapoptotic Bcl-2 in T cells, which can heighten autoimmune disease.
The regulation of T cell survival and apop-tosis is critical for proper immune func-
tion and lymphocyte homeostasis. Various effector molecules regulate the delicate bal-ance between the population expansion and the elimination of reactive T cells during an adaptive immune response. Once a pathogen has been cleared, apoptosis of effector T cells is tightly regulated to maintain peripheral immune tolerance. Disruption of this pro-cess can disturb normal T cell homeostasis, which is deleterious for the health of a per-son. Although increased cell death can result in immunodeficiency, enhanced survival and prolonged T cell activation can promote the development of autoimmune disorders such as multiple sclerosis. In this issue of Nature Immunology, Pei and colleagues describe an important link between the antiapoptotic protein Bcl-2 and the transcriptional regu-lator β-arrestin 1, showing that β-arrestin 1 enhances Bcl2 expression by promoting acetylation of histone H4 at the Bcl2 pro-moter1. Moreover, they show that this link has pathological relevance in both multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), in that β-arrestin 1 –knockout mice are more resistant to dis-ease, whereas overexpression of β-arrestin 1 in transgenic mice leads to increased CD4+ T cell survival and enhanced susceptibility to disease.
Multiple sclerosis is an autoimmune demyelinating disease of the central ner-
vous system thought to be mediated mainly by myelin-reactive CD4+ and CD8+ T cells2. EAE is a well accepted animal model of mul-tiple sclerosis induced by immunization with myelin proteins or peptide epitopes and is mediated by the proinflammatory effects of both CD4+ T helper type 1 cells producing IFN-γ and T helper cells producing IL-17 (refs. 3–6). Increased T cell survival has been linked to increased severity of EAE.
Two separate pathways have been described that control T cell apoptosis. Activation-induced cell death causes death through the activation of death receptors after T cell receptor restimulation, whereas activated T cell–autonomous death is regulated by the ratio between antiapoptotic and proapop-totic Bcl-2 family members in mitochondria. Bcl-2 promotes T cell survival by block-ing the proapoptotic activity of the Bcl-2 family member Bim at the mitochondrial membrane7. Mice that overexpress Bcl-2 specifically in T cells have fewer apoptotic T cells in the central nervous system during EAE induced by myelin oligodendrocyte gly-coprotein and suffer a more severe chronic phase of the disease8.
Although other published studies have shown that Bcl-2 is important in cell survival and apoptosis resistance, the mechanisms controlling expression of this molecule are not fully understood. The findings now presented by Pei and colleagues1 describing epigenetic regulation of Bcl-2 expression by β-arrestin 1 are new and contribute sub-stantially to a more comprehensive under-standing of Bcl-2 regulation. Moreover, the function of β-arrestin 1 in CD4+ T cell sur-vival has not been explored before and adds a new dimension to the understanding of the regulatory mechanism of T cell survival
and broadens the list of functions credited to β-arrestin 1 (Fig. 1).
The β-arrestins are ubiquitously expressed in most tissues and were originally discov-ered as steric inhibitors of G protein–coupled receptor signaling9. As they serve as signal-ing scaffolds, β-arrestins have subsequently been shown to activate signaling pathways independently of G protein activation and have been found to regulate transcription both directly and indirectly9. It has also been shown that stimulation of a specific G protein–coupled receptor, the delta-opi-oid receptor, induces nuclear translocation of β-arrestin 1, which leads to β-arrestin 1 –mediated recruitment of the histone acet-yltransferase p300 to the promoters of the genes encoding p27 and c-Fos, as well as β-arrestin 1–dependent transcription of these genes9,10. In human neuroblastoma cells, activation of the delta-opioid receptor leads to β-arrestin 1–dependent and p27–dependent growth inhibition9,10.
Mechanistically similar, but involving a different gene and cell type, the study by Pei and colleagues here1 provides evidence that β-arrestin 1 epigenetically regulates Bcl2 expression in both naive CD4+ T cells and CD4+ T cells activated with antibodies to CD3 and CD28. As in the previous study10, they find that histone acetyltransferase p300 is important in β-arrestin 1–mediated acet-ylation of H4 and transcription. Although they found this regulation in naive CD4+ T cells1, another study has shown that CD28 costimulation induces the delta-opioid receptor in T cells11, which coupled with the delta-opioid receptor study mentioned above10, indicates that T cell activation could further amplify β-arrestin 1–mediated regu-lation of Bcl-2 in these cells. That result has
Terra J. Frederick and Stephen D. Miller are in the
Department of Microbiology-Immunology and the
Interdepartmental Immunobiology Center, Feinberg
School of Medicine, Northwestern University,
Chicago, Illinois 60611, USA.
e-mail: [email protected]
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been confirmed as unpublished data by Pei and colleagues1, who propose a function for β-arrestin 1 in transmitting environmental signals to influence cellular ‘decisions’ of CD4+ T cells.
Coinciding with β-arrestin 1–mediated Bcl-2 regulation in CD4+ T cells, Pei and colleagues find that cell survival is positively regulated by β-arrestin 1. Naive and acti-vated CD4+ T cells isolated from β-arrestin 1–knockout (Arrb1–/–) or β-arrestin 1– transgenic mice demonstrate increased or decreased survival, respectively. Because Bcl-2 is a known antiapoptotic signaling molecule, it is not unexpected that a positive regulator (β-arrestin 1) of Bcl2 would have a positive effect on T cell survival. However, the finding that CD4+ T cell survival but not CD8+ T cell or thymocyte survival is affected by over- or underexpression of β-arrestin 1 is intriguing. Pei and colleagues do note low expression of β-arrestin 1 in thymocytes and higher nuclear expression of β-arrestin 1 in CD4+ T cells than in CD8+ T cells as plausible explanations for those differences. Because
EAE is believed to be mediated mainly by proinflammatory CD4+ T helper type 1 cells and interleukin 17–producing T helper cells, the higher and lower disease severity, respectively, of β-arrestin 1–transgenic and β-arrestin 1–knockout mice primed with myelin oligodendrocyte glycoprotein is consistent with the idea that enhanced CD4+ T cell survival promotes the progression of autoimmune demyelination.
Expression of β-arrestin 1 has been shown before to be higher in encephalitogenic CD4+ T cells isolated from mice with EAE12. Pei and colleagues now show that β-arrestin 1 expression is much higher in CD4+ T cells from patients with multiple sclerosis and that inhibition of β-arrestin 1 in myelin basic protein–reactive CD4+ T cell clones enhances the susceptibility of these cells to apoptosis1. Thus, combined with the EAE data, the mul-tiple sclerosis findings indicate involvement of β-arrestin 1 in the increased survival and activation of inflammatory CD4+ T cells dur-ing autoimmune demyelination. The authors additionally report but do not show that
β-arrestin 1 modulates the severity of strep-tozotocin-induced type I diabetes, indicating that other autoimmune conditions may also be regulated by β-arrestin 1.
The therapeutic implications of the find-ings by Pei and colleagues6 are uncertain at present. The proposed association between higher expression of β-arrestin 1 and auto-reactive CD4+ T cells in multiple sclerosis is still speculative and awaits confirmation in other autoimmune diseases. On first evalu-ation, it might seem that drugs leading to downregulation of β-arrestin 1 activity could provide a potential therapeutic target for the treatment of multiple sclerosis and perhaps other autoimmune diseases. However, many issues remain concerning the function(s) of β-arrestin 1 in the regulation of CD4+
T cells.As discussed above, the functions of β-
arrestin 1 both in the cytoplasm and nucleus are many and expanding; thus, it is difficult to overlook the possibility that other genes are regulated by β-arrestin 1 in CD4+ T cells. Other investigations have shown that the genes encoding p27 and c-Fos are regulated by nuclear β-arrestin 1 in certain cell types, but Pei and colleagues make no mention of whether these or other genes are transcrip-tionally regulated in CD4+ T cells. Further studies are thus needed to more fully evalu-ate the implications of a β-arrestin 1–tar-geted therapy for autoimmune disease. At present, the practicality of targeting this pathway to treat autoimmune disease would be problematic both because of the myriad signaling pathways affected by β-arrestin 1 and because this pathway is necessary for promoting immune responses to infectious agents. Nevertheless, the data reported by Pei and colleagues1 indicate an important new function for β-arrestin 1 in CD4+ T cell survival.
COMPETING INTERESTS STATEMENTThe authors declare no competing financial interests.
1. Shi, Y. et al. Nat. Immunol. 8, 817–824 (2007). 2. Wekerle, H. Acta Neurol. (Napoli) 13, 197–204
(1991).3. Begolka, W.S., Vanderlugt, C.L., Rahbe, S.M. & Miller, S.D.
J. Immunol. 161, 4437–4446 (1998).4. Park, H. et al. Nat. Immunol. 6, 1133–1141 (2005).5. Chen, Y. et al. J. Clin. Invest. 116, 1317–1326
(2006).6. Langrish, C.L. et al. J. Exp. Med. 201, 233–240
(2005).7. Zhu, Y. et al. Proc. Natl. Acad. Sci. USA 101, 7681–
7686 (2004).8. Okuda, Y., Okuda, M. & Bernard, C.C. J. Neuroimmunol.
131, 115–125 (2002).9. Ma, L. & Pei, G. J. Cell Sci. 120, 213–218 (2007).10. Kang, J. et al. Cell 123, 833–847 (2005).11. Nguyen, K. & Miller, B.C. J. Immunol. 168, 4440–4445
(2002).12. Vroon, A., Lombardi, M.S., Kavelaars, A. & Heijnen,
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792 VOLUME 8 NUMBER 8 AUGUST 2007 NATURE IMMUNOLOGY
TCR
CD3
CD4 CD28 DOR
Mitochondrion
Bcl-2
Bcl-2
Cytochrome crelease and caspase
activation
Apoptosis
β-arrestin 1
β-arrestin 1
p300 CREB
CytoplasmNucleus
H4
AC
Figure 1 Regulation of transcription of Bcl2 by β-arrestin 1. It has been shown that β-arrestin 1 regulates transcription by associating with transcriptional cofactors at promoter regions of specific genes in the nucleus. This model for the direct regulation of transcription by β-arrestin 1 has been reported before for the genes encoding p27 and c-Fos and the associated regulation of growth inhibition in human neuroblastoma cells10. After stimulation of a G protein–coupled receptor, specifically the delta-opioid receptor (DOR), β-arrestin 1 translocates to the nucleus and facilitates the recruitment of p300, a histone acetyltransferase, and subsequent transcription of specific genes. Epigenetic regulation of Bcl2 by β-arrestin 1 in both naive CD4+ T cells and CD4+ T cells activated by antibodies to CD3 and CD28 has now been demonstrated1, indicating a critical function for β-arrestin 1 in CD4+ T cell survival. CD28 costimulation has been shown before to induce the delta-opioid receptor in T cells11, which could further amplify β-arrestin 1–mediated regulation of Bcl-2 in CD4 T cells. TCR, T cell receptor; CREB, cAMP response element–binding protein; H4 AC, acetylated histone H4.
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