title: Out-of-Sequence Signal 3 Paralyzes Primary CD4(+) T-Cell-Dependent Immunity.
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.
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.
authors.forename: Gail D
authors.initials: GD
authors.lastname: Sckisel
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.
authors.forename: Myriam N
authors.initials: MN
authors.lastname: Bouchlaka
authors.affiliation: Department of Radiation-Oncology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.
authors.forename: Arta M
authors.initials: AM
authors.lastname: Monjazeb
authors.affiliation: 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.
authors.forename: Marka
authors.initials: M
authors.lastname: Crittenden
authors.affiliation: 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.
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Curti
authors.affiliation: Department of Microbiology and Immunology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA.
authors.forename: Danice E C
authors.initials: DE
authors.lastname: Wilkins
authors.affiliation: Department of Microbiology and Immunology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA.
authors.forename: Kory A
authors.initials: KA
authors.lastname: Alderson
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.
authors.forename: Can M
authors.initials: CM
authors.lastname: Sungur
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Ames
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.
authors.forename: Annie
authors.initials: A
authors.lastname: Mirsoian
authors.affiliation: Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Reddy
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3050, Australia.
authors.forename: Warren
authors.initials: W
authors.lastname: Alexander
authors.affiliation: 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.
authors.forename: Athena
authors.initials: A
authors.lastname: Soulika
authors.affiliation: Department of Pediatrics, Division of Blood and Marrow Transplantation and the University of Minnesota Cancer Center, Minneapolis, MN 55455, USA.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Laboratory of Genetics, National Institute on Aging, Baltimore, MD 21224, USA.
authors.forename: Dan L
authors.initials: DL
authors.lastname: Longo
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Wiltrout
authors.affiliation: 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: wmjmurphy@ucdavis.edu.
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D017635:Clonal Anergy; D005260:Female; D006566:Herpesviridae Infections / Q000276:immunology / Q000628:therapy*; D006801:Humans; D007111:Immunity, Cellular; D007156:Immunologic Memory; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007376:Interleukin-2 / Q000008:administration & dosage; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D018146:Muromegalovirus / Q000276:immunology*; D016032:Randomized Controlled Trials as Topic; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000276:immunology / Q000628:therapy*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D019562:Viral Load / Q000276:immunology
chemical_list: D000941:Antigens; D007376:Interleukin-2; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007371:Interferon-gamma