{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T14:13:19Z","timestamp":1762956799162,"version":"build-2065373602"},"reference-count":51,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T00:00:00Z","timestamp":1642118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["R01AI118774"],"award-info":[{"award-number":["R01AI118774"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by dysregulated T and B lymphocytes. Type I interferons (IFN-I) have been shown to play important pathogenic roles in both SLE patients and mouse models of lupus. Recent studies have shown that B cell intrinsic responses to IFN-I are enough to drive B cell differentiation into autoantibody-secreting memory B cells and plasma cells, although lower levels of residual auto-reactive cells remain present. We speculated that IFN-I stimulation of T cells would similarly drive specific T-cell associated lupus phenotypes including the upregulation of T follicular helper cells and Th17, thereby affecting autoantibody production and the development of glomerulonephritis. Using the B6.Nba2 mouse model of lupus, we evaluated disease parameters in T cell specific IFN-I receptor (IFNAR)-deficient mice (cKO). Surprisingly, all measured CD4+ T cell abnormalities and associated intra-splenic cytokine levels (IFN\u03b3, IL-6, IL-10, IL-17, IL-21) were unchanged and thus independent of IFN-I. In contrast B6.Nba2 cKO mice displayed reduced levels of effector CD8+ T cells and increased levels of Foxp3+ CD8+ regulatory T cells, suggesting that IFN-I induced signaling specifically affecting CD8+ T cells. These data suggest a role for both pathogenic and immunosuppressive CD8+ T cells in Nba2-driven autoimmunity, providing a model to further evaluate the role of these cell subsets during lupus-like disease development in vivo.<\/jats:p>","DOI":"10.3390\/ijms23020874","type":"journal-article","created":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T12:34:04Z","timestamp":1642163644000},"page":"874","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Spontaneous CD4+ T Cell Activation and Differentiation in Lupus-Prone B6.Nba2 Mice Is IFNAR-Independent"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0368-4175","authenticated-orcid":false,"given":"Emma J.","family":"Keller","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, Cleveland Clinic Lerner at Case Western Reserve University, Cleveland, OH 44195, USA"},{"name":"Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nina","family":"Dvorina","sequence":"additional","affiliation":[{"name":"Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Trine N.","family":"J\u00f8rgensen","sequence":"additional","affiliation":[{"name":"Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.cyto.2014.12.027","article-title":"Th1\/Th2\/Th17\/Treg cytokine imbalance in systemic lupus erythematosus (SLE) patients: Correlation with disease activity","volume":"72","author":"Talaat","year":"2015","journal-title":"Cytokine"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"R53","DOI":"10.1186\/ar2964","article-title":"Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus","volume":"12","author":"Shah","year":"2010","journal-title":"Arthritis Res. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"103","DOI":"10.4049\/jimmunol.143.1.103","article-title":"T cell receptor alpha\/beta expressing double-negative (CD4-\/CD8-) and CD4+ T helper cells in humans augment the production of pathogenic anti-DNA autoantibodies associated with lupus nephritis","volume":"143","author":"Shivakumar","year":"1989","journal-title":"J. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2859","DOI":"10.1038\/s41467-020-16636-4","article-title":"Systemic lupus erythematosus favors the generation of IL-17 producing double negative T cells","volume":"11","author":"Li","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1177\/0961203308089400","article-title":"CD8+CD28-, suppressive T cells in systemic lupus erythematosus","volume":"17","author":"Tulunay","year":"2008","journal-title":"Lupus"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.clim.2008.01.019","article-title":"Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: Implications for Th17-mediated inflammation in auto-immunity","volume":"127","author":"Wong","year":"2008","journal-title":"Clin. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1111\/j.1365-2249.2008.03758.x","article-title":"Overexpression of interleukin-12 and T helper 1 predominance in lupus nephritis","volume":"154","author":"Tucci","year":"2008","journal-title":"Clin. Exp. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1177\/0961203314567750","article-title":"Circulating CXCR5+CD4+helper T cells in systemic lupus erythematosus patients share phenotypic properties with germinal center follicular helper T cells and promote antibody production","volume":"24","author":"Zhang","year":"2015","journal-title":"Lupus"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1002\/art.39020","article-title":"Circulating Follicular Helper\u2013Like T Cells in Systemic Lupus Erythematosus: Association With Disease Activity","volume":"67","author":"Choi","year":"2015","journal-title":"Arthritis Rheumatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.3899\/jrheum.131025","article-title":"Increased Interleukin 21 and Follicular Helper T-like Cells and Reduced Interleukin 10+ B cells in Patients with New-onset Systemic Lupus Erythematosus","volume":"41","author":"Wang","year":"2014","journal-title":"J. Rheumatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2694","DOI":"10.4049\/jimmunol.169.5.2694","article-title":"The Major Murine Systemic Lupus Erythematosus Susceptibility Locus Sle1 Results in Abnormal Functions of Both B and T Cells","volume":"169","author":"Sobel","year":"2002","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1002\/art.38989","article-title":"Sialic acid-binding immunoglobulin-type lectin H-positive plasmacytoid dendritic cells drive spontaneous lupus-like disease development in B6.Nba2 mice","volume":"67","author":"Davison","year":"2015","journal-title":"Arthritis Rheumatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3371","DOI":"10.3389\/fimmu.2020.616064","article-title":"Partial Protection From Lupus-Like Disease by B-Cell Specific Type I Interferon Receptor Deficiency","volume":"11","author":"Keller","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1073\/pnas.0903158107","article-title":"Homeostatic imbalance of regulatory and effector T cells due to IL-2 deprivation amplifies murine lupus","volume":"107","author":"Humrich","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3053","DOI":"10.1002\/eji.1830251111","article-title":"Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells","volume":"25","author":"Sadlack","year":"1995","journal-title":"Eur. J. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.1002\/art.20359","article-title":"Dichotomous effects of complete versus partial class II major histocompatibility complex deficiency on circulating autoantibody levels in autoimmune-prone mice","volume":"50","author":"Stohl","year":"2004","journal-title":"Arthritis Rheum."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1002\/art.38955","article-title":"Function of the Th17\/interleukin-17A immune response in murine lupus nephritis","volume":"67","author":"Schmidt","year":"2015","journal-title":"Arthritis Rheumatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2168","DOI":"10.4049\/jimmunol.1400977","article-title":"IL-2 Protects Lupus-Prone Mice from Multiple End-Organ Damage by Limiting CD4\u2212CD8\u2212 IL-17\u2013Producing T Cells","volume":"193","author":"Mizui","year":"2014","journal-title":"J. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5227","DOI":"10.1038\/s41598-019-41534-1","article-title":"Inhibition of IL-17 ameliorates systemic lupus erythematosus in Roquin(san\/san) mice through regulating the balance of TFH cells, GC B cells, Treg and Breg","volume":"9","author":"Lee","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1084\/jem.154.3.791","article-title":"Analysis of T cell function in autoimmune murine strains. Defects in production and responsiveness to interleukin 2","volume":"154","author":"Altman","year":"1981","journal-title":"J. Exp. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"796","DOI":"10.4049\/jimmunol.1901175","article-title":"Type II but Not Type I IFN Signaling Is Indispensable for TLR7-Promoted Development of Autoreactive B Cells and Systemic Autoimmunity","volume":"204","author":"Chodisetti","year":"2020","journal-title":"J. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1084\/jem.20081886","article-title":"Follicular helper T cells are required for systemic autoimmunity","volume":"206","author":"Linterman","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2848","DOI":"10.4049\/jimmunol.171.6.2848","article-title":"Involvement of Inducible Costimulator-B7 Homologous Protein Costimulatory Pathway in Murine Lupus Nephritis","volume":"171","author":"Iwai","year":"2003","journal-title":"J. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.4049\/jimmunol.160.5.2158","article-title":"Anti-CD40 ligand antibody treatment of SNF1 mice with established nephritis: Preservation of kidney function","volume":"160","author":"Kalled","year":"1998","journal-title":"J. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/sj.gene.6364430","article-title":"Type I interferon signaling is involved in the spontaneous development of lupus-like disease in B6.Nba2 and (B6.Nba2\u00d7 NZW)F(1) mice","volume":"8","author":"Jorgensen","year":"2007","journal-title":"Genes Immun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6021","DOI":"10.4049\/jimmunol.0803872","article-title":"Deficiency of type I IFN receptor in lupus-prone New Zealand mixed 2328 mice decreases dendritic cell numbers and activation and protects from disease","volume":"183","author":"Agrawal","year":"2009","journal-title":"J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1948","DOI":"10.1002\/eji.200837925","article-title":"Systemic IFN-alpha drives kidney nephritis in B6.Sle123 mice","volume":"38","author":"Fairhurst","year":"2008","journal-title":"Eur. J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.4049\/jimmunol.174.5.2499","article-title":"IFN-alpha induces early lethal lupus in preautoimmune (New Zealand Black x New Zealand White) F1 but not in BALB\/c mice","volume":"174","author":"Mathian","year":"2005","journal-title":"J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1084\/jem.20021996","article-title":"Type-I Interferon Receptor Deficiency Reduces Lupus-like Disease in NZB Mice","volume":"197","author":"Baccala","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1080\/08916930310001624665","article-title":"Inhibition of lupus by genetic alteration of the interferon-alpha\/beta receptor","volume":"36","author":"Kono","year":"2003","journal-title":"Autoimmunity"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1084\/jem.20021553","article-title":"Interferon and granulopoiesis signatures in systemic lupus erythematosus blood","volume":"197","author":"Bennett","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2610","DOI":"10.1073\/pnas.0337679100","article-title":"Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus","volume":"100","author":"Baechler","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1084\/jem.189.3.521","article-title":"Type I interferons keep activated T cells alive","volume":"189","author":"Marrack","year":"1999","journal-title":"J. Exp. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3315","DOI":"10.4049\/jimmunol.176.6.3315","article-title":"Cutting Edge: The direct action of type I IFN on CD4 T cells is critical for sustaining clonal expansion in response to a viral but not a bacterial infection","volume":"176","author":"Kolumam","year":"2006","journal-title":"J. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1084\/jem.20050821","article-title":"Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection","volume":"202","author":"Kolumam","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4682","DOI":"10.4049\/jimmunol.176.8.4682","article-title":"Direct stimulation of T cells by type I IFN enhances the CD8+ T cell response during cross-priming","volume":"176","author":"Durand","year":"2006","journal-title":"J. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2156","DOI":"10.4049\/jimmunol.1300675","article-title":"Type I IFN induces binding of STAT1 to Bcl6: Divergent roles of STAT family transcription factors in the T follicular helper cell genetic program","volume":"192","author":"Nakayamada","year":"2014","journal-title":"J. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1038\/nature14468","article-title":"T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection","volume":"523","author":"McKinney","year":"2015","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1016\/j.humimm.2008.08.284","article-title":"Induction of immune tolerance by activation of CD8+ T suppressor\/regulatory cells in lupus-prone mice","volume":"69","author":"Skaggs","year":"2008","journal-title":"Hum. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.autrev.2010.03.006","article-title":"CD8+ Tregs in lupus, autoimmunity, and beyond","volume":"9","author":"Dinesh","year":"2010","journal-title":"Autoimmun. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2069","DOI":"10.4049\/jimmunol.180.4.2069","article-title":"pConsensus peptide induces tolerogenic CD8+ T cells in lupus-prone (NZB x NZW)F1 mice by differentially regulating Foxp3 and PD1 molecules","volume":"180","author":"Singh","year":"2008","journal-title":"J. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4884","DOI":"10.1172\/JCI120859","article-title":"Kidney-infiltrating T cells in murine lupus nephritis are metabolically and functionally exhausted","volume":"128","author":"Tilstra","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"775","DOI":"10.4049\/jimmunol.0901322","article-title":"Development of murine lupus involves the combined genetic contribution of the SLAM and FcgammaR intervals within the Nba2 autoimmune susceptibility locus","volume":"184","author":"Jorgensen","year":"2010","journal-title":"J. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1038\/gene.2011.4","article-title":"Interferon-inducible gene 202b controls CD8(+) T cell-mediated suppression in anti-DNA Ig peptide-treated (NZB \u00d7 NZW) F1 lupus mice","volume":"12","author":"Dinesh","year":"2011","journal-title":"Genes Immun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2362","DOI":"10.1002\/art.22654","article-title":"Predominance of CD8+ T lymphocytes among periglomerular infiltrating cells and link to the prognosis of class III and class IV lupus nephritis","volume":"56","author":"Couzi","year":"2007","journal-title":"Arthritis Rheum."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1002\/ana.21652","article-title":"T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-beta","volume":"65","author":"Durelli","year":"2009","journal-title":"Ann. Neurol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.humimm.2003.12.001","article-title":"Nonantigen specific CD8+ T suppressor lymphocytes originate from CD8+CD28- T cells and inhibit both T-cell proliferation and CTL function","volume":"65","author":"Filaci","year":"2004","journal-title":"Hum. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/S0171-2985(98)80052-1","article-title":"Effects of administration of monoclonal antibodies (anti-CD4 or anti-CD8) on the development of autoimmune diseases in (NZW x BXSB)F1 mice","volume":"198","author":"Adachi","year":"1998","journal-title":"Immunobiology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"7728","DOI":"10.4049\/jimmunol.175.11.7728","article-title":"Tolerogenic treatment of lupus mice with consensus peptide induces Foxp3-expressing, apoptosis-resistant, TGFbeta-secreting CD8+ T cell suppressors","volume":"175","author":"Hahn","year":"2005","journal-title":"J. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/S1074-7613(01)00126-1","article-title":"Type i interferons potently enhance humoral immunity and can promote isotype switching by stimulating dendritic cells in vivo","volume":"14","author":"Schiavoni","year":"2001","journal-title":"Immunity"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/S1074-7613(01)00227-8","article-title":"A Critical Role for Dnmt1 and DNA Methylation in T Cell Development, Function, and Survival","volume":"15","author":"Lee","year":"2001","journal-title":"Immunity"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/2\/874\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:27:21Z","timestamp":1760362041000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/2\/874"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,14]]},"references-count":51,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["ijms23020874"],"URL":"https:\/\/doi.org\/10.3390\/ijms23020874","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2022,1,14]]}}}