Out-of-Sequence Signal 3 Paralyzes Primary CD4(+) T-Cell-Dependent Immunity.
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Authors
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Sckisel, Gail D1
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Bouchlaka, Myriam N1
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Monjazeb, Arta M2
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Crittenden, Marka3
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Curti, Brendan D3
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Wilkins, Danice E C4
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Alderson, Kory A4
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Sungur, Can M1
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Ames, Erik1
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Mirsoian, Annie1
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Reddy, Abhinav1
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Alexander, Warren5
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Soulika, Athena6
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Blazar, Bruce R7
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Longo, Dan L8
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Wiltrout, Robert H9
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Murphy, William J10
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1
Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.
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2
Department of Radiation-Oncology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.
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3
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, OR 97213, USA; The Oregon Clinic, Portland, OR 97220, USA.
,
(Chile)
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4
Department of Microbiology and Immunology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA.
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5
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3050, Australia.
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(Australia)
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6
Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA; Institute for Pediatric Regenerative Medicine, Shriner's Hospitals for Children - Northern California, Sacramento, CA 95817, USA.
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7
Department of Pediatrics, Division of Blood and Marrow Transplantation and the University of Minnesota Cancer Center, Minneapolis, MN 55455, USA.
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8
Laboratory of Genetics, National Institute on Aging, Baltimore, MD 21224, USA.
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9
Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA.
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10
Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA; Department of Internal Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA. Electronic address: [email protected]
- Type
- Published Article
- Journal
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Immunity
- Publication Date
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Aug 18, 2015
- Volume
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43
- Issue
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2
- Pages
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240–250
- Identifiers
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DOI: 10.1016/j.immuni.2015.06.023
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PMID: 26231116
- Source
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Medline
- License
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Unknown
Abstract
Primary T cell activation involves the integration of three distinct signals delivered in sequence: (1) antigen recognition, (2) costimulation, and (3) cytokine-mediated differentiation and expansion. Strong immunostimulatory events such as immunotherapy or infection induce profound cytokine release causing "bystander" T cell activation, thereby increasing the potential for autoreactivity and need for control. We show that during strong stimulation, a profound suppression of primary CD4(+) T-cell-mediated immune responses ensued and was observed across preclinical models and patients undergoing high-dose interleukin-2 (IL-2) therapy. This suppression targeted naive CD4(+) but not CD8(+) T cells and was mediated through transient suppressor of cytokine signaling-3 (SOCS3) inhibition of the STAT5b transcription factor signaling pathway. These events resulted in complete paralysis of primary CD4(+) T cell activation, affecting memory generation and induction of autoimmunity as well as impaired viral clearance. These data highlight the critical regulation of naive CD4(+) T cells during inflammatory conditions.
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
This record was last updated on 06/09/2018 and may not reflect the most current and accurate biomedical/scientific data available from NLM.
The corresponding record at NLM can be accessed at
https://www.ncbi.nlm.nih.gov/pubmed/26231116
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