title: CD8+ regulatory T cells induced by T cell vaccination protect against autoimmune nephritis.
abstract: Autoreactive T cells play a pivotal role in the pathogenesis of autoimmune kidney disease. T cell vaccination (TCV) may limit autoimmune disease and induce CD8+ regulatory T cells (Tregs). We used Heymann nephritis (HN), a rat model of human membranous nephritis, to study the effects of TCV on autoimmune kidney disease. We harvested CD4+ T cells from renal tubular antigen (Fx1A) -immunized rats and activated these cells in vitro to express the MHC Class Ib molecule Qa-1. Vaccination of Lewis rats with these autoreactive Fx1A-induced T cells protected against HN, whereas control-primed T cells did not. Rats that underwent TCV had lower levels of proteinuria and serum creatinine and significantly less glomerulosclerosis, tubular damage, and interstitial infiltrates. Furthermore, these rats expressed less IFN-γ and IL-6 in splenocytes, whereas the numbers of Tregs and the expression of Foxp3 were unchanged. In vitro cytotoxicity assays showed CD8+ T cell-mediated elimination of Qa-1-expressing CD4+ T cells. In vivo, TCV abrogated the increase in Qa-1-expressing CXCR5+ TFH cells observed in HN compared with controls. Taken together, these results suggest that TCV protects against autoimmune kidney disease by targeting Qa-1-expressing autoreactive CD4+ cells.
authors.affiliation: Centre for Kidney Research, Children's Hospital at Westmead, Westmead, Sydney, NSW 2145, Australia.
authors.forename: Yuan Min
authors.initials: YM
authors.lastname: Wang
authors.forename: Geoff Yu
authors.initials: GY
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Hu
authors.forename: Tania
authors.initials: T
authors.lastname: Polhill
authors.forename: Andrew
authors.initials: A
authors.lastname: Sawyer
authors.forename: Jimmy Jianheng
authors.initials: JJ
authors.lastname: Zhou
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Saito
authors.forename: Debbie
authors.initials: D
authors.lastname: Watson
authors.forename: Huiling
authors.initials: H
authors.lastname: Wu
authors.forename: Ya
authors.initials: Y
authors.lastname: Wang
authors.forename: Xin Maggie
authors.initials: XM
authors.lastname: Wang
authors.forename: Yiping
authors.initials: Y
authors.lastname: Wang
authors.forename: David C H
authors.initials: DC
authors.lastname: Harris
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Alexander
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015433:Glomerulonephritis, Membranous / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000276:immunology*; D012494:Sampling Studies; D013601:T-Lymphocytes / Q000276:immunology; D014611:Vaccination / Q000379:methods*
chemical_list: D001323:Autoantibodies; D016207:Cytokines; D016693:Receptors, Antigen, T-Cell, alpha-beta