title: Interferon-inducible gene 202b controls CD8(+) T cell-mediated suppression in anti-DNA Ig peptide-treated (NZB × NZW) F1 lupus mice.
abstract: Administration of an artificial peptide (pConsensus) based on anti-DNA IgG sequences that contain major histocompatibility complex class I and class II T-cell determinants, induces immune tolerance in NZB/NZW F1 female (BWF1) mice. To understand the molecular basis of CD8(+) Ti-mediated suppression, we previously performed microarray analysis to identify genes that were differentially expressed following tolerance induction with pCons. CD8(+) T cells from mice tolerized with pCons showed more than two-fold increase in Ifi202b mRNA, an interferon inducible gene, versus cells from untolerized mice. Ifi202b expression increased through weeks 1-4 after tolerization and then decreased, reapproaching baseline levels at 6 weeks. In vitro polyclonal activation of tolerized CD8(+) T cells significantly increased Ifi202b mRNA expression. Importantly, silencing of Ifi202b abrogated the suppressive capacity of CD8(+) Ti cells. This was associated with decreased expression of Foxp3, and decreased gene and protein expression of transforming growth factor (TGF)β and interleukin-2 (IL-2), but not of interferon (IFN)-γ, IL-10, or IL-17. Silencing of another IFN-induced gene upregulated in tolerized CD8(+) T cells, IFNAR1, had no effect on the ability of CD8(+) T cells to suppress autoantibody production. Our findings indicate a potential role for Ifi202b in the suppressive capacity of peptide-induced regulatory CD8(+) Ti cells through effects on the expression of Foxp3 and the synthesis of TGFβ.
authors.affiliation: Division of Rheumatology, Department of Medicine at the David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Dinesh
authors.forename: B H
authors.initials: BH
authors.lastname: Hahn
authors.forename: A
authors.initials: A
authors.lastname: La Cava
authors.forename: R P
authors.initials: RP
authors.lastname: Singh
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis* / Q000737:chemistry; D001402:B-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D020868:Gene Silencing; D007108:Immune Tolerance / Q000187:drug effects / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000276:immunology / Q000494:pharmacology; D007155:Immunologic Factors / Q000276:immunology / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008814:Mice, Inbred NZB; D010455:Peptides; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism
chemical_list: D000974:Antibodies, Antinuclear; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C092537:Ifi202b protein, mouse; D007135:Immunoglobulin Variable Region; D007155:Immunologic Factors; D047908:Intracellular Signaling Peptides and Proteins; D010455:Peptides; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D004247:DNA