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Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.).

ABSTRACT: Cereblon (CRBN), the molecular target of lenalidomide and pomalidomide, is a substrate receptor of the cullin ring E3 ubiquitin ligase complex, CRL4(CRBN) . T cell co-stimulation by lenalidomide or pomalidomide is cereblon dependent: however, the CRL4(CRBN) substrates responsible for T cell co-stimulation have yet to be identified. Here we demonstrate that interaction of the transcription factors Ikaros (IKZF1, encoded by the IKZF1 gene) and Aiolos (IKZF3, encoded by the IKZF3 gene) with CRL4(CRBN) is induced by lenalidomide or pomalidomide. Each agent promotes Aiolos and Ikaros binding to CRL4(CRBN) with enhanced ubiquitination leading to cereblon-dependent proteosomal degradation in T lymphocytes. We confirm that Aiolos and Ikaros are transcriptional repressors of interleukin-2 expression. The findings link lenalidomide- or pomalidomide-induced degradation of these transcriptional suppressors to well documented T cell activation. Importantly, Aiolos could serve as a proximal pharmacodynamic marker for lenalidomide and pomalidomide, as healthy human subjects administered lenalidomide demonstrated Aiolos degradation in their peripheral T cells. In conclusion, we present a molecular model in which drug binding to cereblon results in the interaction of Ikaros and Aiolos to CRL4(CRBN) , leading to their ubiquitination, subsequent proteasomal degradation and T cell activation.

SUBMITTER: Gandhi AK

PROVIDER: S-EPMC4232904 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.).

Gandhi Anita K AK Kang Jian J Havens Courtney G CG Conklin Thomas T Ning Yuhong Y Wu Lei L Ito Takumi T Ando Hideki H Waldman Michelle F MF Thakurta Anjan A Klippel Anke A Handa Hiroshi H Daniel Thomas O TO Schafer Peter H PH Chopra Rajesh R

British journal of haematology 20131213 6

Cereblon (CRBN), the molecular target of lenalidomide and pomalidomide, is a substrate receptor of the cullin ring E3 ubiquitin ligase complex, CRL4(CRBN) . T cell co-stimulation by lenalidomide or pomalidomide is cereblon dependent: however, the CRL4(CRBN) substrates responsible for T cell co-stimulation have yet to be identified. Here we demonstrate that interaction of the transcription factors Ikaros (IKZF1, encoded by the IKZF1 gene) and Aiolos (IKZF3, encoded by the IKZF3 gene) with CRL4(CR ...[more]

PMID: 24328678

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Project description:HIV persists in people living with HIV (PLHIV) on antiretroviral therapy (ART) in long-lived and proliferating latently infected CD4+ T cells that selectively express pro-survival proteins, including the zinc finger proteins, Ikaros and Aiolos. In this study, we investigated whether pomalidomide, an immunomodulatory agent that induces degradation of Ikaros and Aiolos, could increase the death of HIV-infected cells and/or reverse HIV latency. Using an in vitro model of CD4+ T cells infected with a green fluorescent protein (GFP) reporter virus, pomalidomide increased the expression of the pro-survival protein B cell lymphoma (Bcl)-2 and did not increase apoptosis of GFP+ HIV productively infected CD4+ T cells. Pomalidomide also increased the expression of CD155 and UL16-binding protein (ULBP) stress proteins on GFP+ HIV productively infected CD4+ T cells, but this did not translate to enhanced clearance following co-culture with a natural killer (NK) cell line. Using CD4+ T cells from PLHIV on ART, pomalidomide ex vivo activated memory CD4+ T cells resulting in elevated HLA-DR expression and induced CD4+ T cell proliferation but only in the presence of T cell receptor stimulation with anti-CD3 and anti-CD28. There was no effect on cell-associated HIV RNA or the frequency of intact HIV DNA. In conclusion, despite an increase in stress protein expression, promoting Ikaros and Aiolos degradation in CD4+ T cells using pomalidomide did not directly induce apoptosis of HIV-infected cells or induce HIV latency reversal.IMPORTANCEPeople living with HIV (PLHIV) require lifelong antiretroviral therapy (ART) due to the persistence of latently infected cells. The zinc finger proteins, Ikaros and Aiolos, have recently been implicated in promoting the persistence of latently infected cells. In this study, we investigated the effects of pomalidomide, an immunomodulatory imide drug that induces the degradation of Ikaros and Aiolos, on HIV latency reversal and death of infected cells. Using CD4+ T cells from people living with HIV on suppressive antiretroviral therapy, as well as an in vitro model of productive HIV infection, we found that pomalidomide induced T cell activation and expression of stress proteins but no evidence of latency reversal or selective death of infected cells.

Dataset Information

Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.).

Publications

Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.).

Similar Datasets

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