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Out-of-Sequence Signal 3 Paralyzes Primary CD4(+) T-Cell-Dependent Immunity.

Authors
  • Sckisel, Gail D1
  • Bouchlaka, Myriam N1
  • Monjazeb, Arta M2
  • Crittenden, Marka3
  • Curti, Brendan D3
  • Wilkins, Danice E C4
  • Alderson, Kory A4
  • Sungur, Can M1
  • Ames, Erik1
  • Mirsoian, Annie1
  • Reddy, Abhinav1
  • Alexander, Warren5
  • Soulika, Athena6
  • Blazar, Bruce R7
  • Longo, Dan L8
  • Wiltrout, Robert H9
  • Murphy, William J10
  • 1 Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.
  • 2 Department of Radiation-Oncology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.
  • 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)
  • 4 Department of Microbiology and Immunology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA.
  • 5 The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3050, Australia. , (Australia)
  • 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.
  • 7 Department of Pediatrics, Division of Blood and Marrow Transplantation and the University of Minnesota Cancer Center, Minneapolis, MN 55455, USA.
  • 8 Laboratory of Genetics, National Institute on Aging, Baltimore, MD 21224, USA.
  • 9 Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA.
  • 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
Immunity
Publication Date
Aug 18, 2015
Volume
43
Issue
2
Pages
240–250
Identifiers
DOI: 10.1016/j.immuni.2015.06.023
PMID: 26231116
Source
Medline
License
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.

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