Glycogen Synthase Kinase 3 Inactivation Drives T-bet-Mediated Downregulation of Co-receptor PD-1 to Enhance CD8 Cytolytic T Cell ResponsesReportar como inadecuado


Glycogen Synthase Kinase 3 Inactivation Drives T-bet-Mediated Downregulation of Co-receptor PD-1 to Enhance CD8  Cytolytic T Cell Responses


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Publication Date: 2016-02-16

Journal Title: Immunity

Publisher: Elsevier (Cell Press)

Volume: 44

Issue: 2

Pages: 274-286

Language: English

Type: Article

Metadata: Show full item record

Citation: Taylor, A., Harker, J. A., Chanthong, K., Stevenson, P. G., Zuniga, E. I., & Rudd, C. E. (2016). Glycogen Synthase Kinase 3 Inactivation Drives T-bet-Mediated Downregulation of Co-receptor PD-1 to Enhance CD8+ Cytolytic T Cell Responses. Immunity, 44 (2), 274-286.

Description: This is the final version of the article. It first appeared from Cell Press via http://dx.doi.org/10.1016/j.immuni.2016.01.018

Abstract: Despite the importance of the co-receptor PD-1 in T cell immunity, the upstream signaling pathway that regulates PD-1 expression has not been defined. Glycogen synthase kinase 3 (GSK-3, isoforms α and β) is a serine-threonine kinase implicated in cellular processes. Here, we identified GSK-3 as a key upstream kinase that regulated PD-1 expression in CD8+ T cells. GSK-3 siRNA downregulation, or inhibition by small molecules, blocked PD-1 expression, resulting in increased CD8+ cytotoxic T lymphocyte (CTL) function. Mechanistically, GSK-3 inactivation increased Tbx21 transcription, promoting enhanced T-bet expression and subsequent suppression of Pdcd1 (encodes PD-1) transcription in CD8+ CTLs. Injection of GSK-3 inhibitors in mice increased in vivo CD8+ OT-I CTL function and the clearance of murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 and reversed T cell exhaustion. Our findings identify GSK-3 as a regulator of PD-1 expression and demonstrate the applicability of GSK-3 inhibitors in the modulation of PD-1 in immunotherapy.

Sponsorship: C.E.R. was supported by Wellcome Trust 092627/Z/10/Z, J.A.H. by an Irvington Institute Postdoctoral Fellowship from the Cancer Research Institute (New York), and E.I.Z. by a Leukemia and Lymphoma Society Scholar Award and a grant from the NIH AI081923. We thank Dr. Graham Lord (King’s College London) for the kind gift of the Ifng CNS-12 promoter.

Identifiers:

This record's URL: http://dx.doi.org/10.1016/j.immuni.2016.01.018https://www.repository.cam.ac.uk/handle/1810/253803

Rights: Attribution 2.0 UK: England & Wales

Licence URL: http://creativecommons.org/licenses/by/2.0/uk/





Autor: Taylor, AlisonHarker, James A.Chanthong, KittiphatStevenson, Philip G.Zuniga, Elina I.Rudd, Christopher E.

Fuente: https://www.repository.cam.ac.uk/handle/1810/253803



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