title: Age-Associated Failure To Adjust Type I IFN Receptor Signaling Thresholds after T Cell Activation.
abstract: With increasing age, naive CD4 T cells acquire intrinsic defects that compromise their ability to respond and differentiate. Type I IFNs, pervasive constituents of the environment in which adaptive immune responses occur, are known to regulate T cell differentiation and survival. Activated naive CD4 T cells from older individuals have reduced responses to type I IFN, a defect that develops during activation and that is not observed in quiescent naive CD4 T cells. Naive CD4 T cells from young adults upregulate the expression of STAT1 and STAT5 after activation, lowering their threshold to respond to type I IFN stimulation. The heightened STAT signaling is critical to maintain the expression of CD69 that regulates lymphocyte egress and the ability to produce IL-2 and to survive. Although activation of T cells from older adults also induces transcription of STAT1 and STAT5, failure to exclude SHP-1 from the signaling complex blunts their type I IFN response. In summary, our data show that type I IFN signaling thresholds in naive CD4 T cells after activation are dynamically regulated to respond to environmental cues for clonal expansion and memory cell differentiation. Naive CD4 T cells from older adults have a defect in this threshold calibration. Restoring their ability to respond to type I IFN emerges as a promising target to restore T cell responses and to improve the induction of T cell memory.
authors.affiliation: Department of Medicine, Palo Alto Veterans Administration Health Care System, Palo Alto, CA 94304; and Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Guangjin
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Medicine, Palo Alto Veterans Administration Health Care System, Palo Alto, CA 94304; and Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Jihang
authors.initials: J
authors.lastname: Ju
authors.affiliation: Department of Medicine, Palo Alto Veterans Administration Health Care System, Palo Alto, CA 94304; and Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Weyand
authors.affiliation: Department of Medicine, Palo Alto Veterans Administration Health Care System, Palo Alto, CA 94304; and Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305 jgoronzy@stanford.edu.
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Goronzy
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000276:immunology*; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D005260:Female; D006801:Humans; D007370:Interferon Type I / Q000276:immunology*; D007376:Interleukin-2 / Q000096:biosynthesis; D037181:Lectins, C-Type / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000096:biosynthesis; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000096:biosynthesis; D050799:STAT5 Transcription Factor / Q000096:biosynthesis; D055815:Young Adult; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D007370:Interferon Type I; D007376:Interleukin-2; D037181:Lectins, C-Type; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D053633:Receptor, Interferon alpha-beta; D050794:STAT1 Transcription Factor; D050799:STAT5 Transcription Factor; D000099192:CD69 Antigens; C508594:IL2 protein, human; C494079:STAT1 protein, human; C509249:PTPN6 protein, human