title: IL-7- and IL-15-mediated TCR sensitization enables T cell responses to self-antigens.
abstract: Regulation of the ERK pathway is intimately involved in determining whether TCR stimulation is productive or induces anergy. T cells from patients with rheumatoid arthritis (RA) have increased ERK responsiveness, which may be relevant for disease pathogenesis. Inflammatory cytokines such as TNF-α did not reproduce the TCR hypersensitivity typical for RA in T cells from healthy individuals. In contrast, priming with the homeostatic cytokines (HCs) IL-7 and IL-15 amplified ERK phosphorylation to TCR stimulation 2- to 3-fold. The underlying mechanism involved a priming of the SOS-dependent amplification loop of RAS activation. The sensitization of the TCR signaling pathway has downstream consequences, such as increased proliferation and preferential Th1 differentiation. Importantly, priming with IL-7 or IL-15 enabled T cell responses to autoantigens associated with RA. Production of HCs is induced in lymphopenic conditions, which have been shown to predispose for autoimmunity and which appear to be present in the preclinical stages of RA. We propose that HCs, possibly induced by lymphopenia, decrease the signaling threshold for TCR activation and are thereby partly responsible for autoimmunity in RA.
authors: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors: Pratima
authors: P
authors: Deshpande
authors: Mary M
authors: MM
authors: Cavanagh
authors: Sabine
authors: S
authors: Le Saux
authors: Karnail
authors: K
authors: Singh
authors: Cornelia M
authors: CM
authors: Weyand
authors: Jörg J
authors: JJ
authors: Goronzy
mesh_terms: D001324:Autoantigens / Q000502:physiology*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology; D006801:Humans; D019409:Interleukin-15 / Q000502:physiology*; D015851:Interleukin-7 / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D020837:SOS1 Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D020664:Son of Sevenless Proteins / Q000235:genetics / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D015854:Up-Regulation / Q000276:immunology
chemical_list: D001324:Autoantigens; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; C569274:IL15 protein, human; C508605:IL7 protein, human; D019409:Interleukin-15; D015851:Interleukin-7; C491790:RASGRP1 protein, human; D011948:Receptors, Antigen, T-Cell; D020837:SOS1 Protein; D020664:Son of Sevenless Proteins