CD8+ regulatory T cells induced by T cell vaccination protect against autoimmune nephritis

J Am Soc Nephrol. 2012 Jun;23(6):1058-67. doi: 10.1681/ASN.2011090914. Epub 2012 Apr 5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Autoantibodies / immunology
  • Autoantibodies / metabolism
  • Autoimmune Diseases / immunology*
  • Autoimmune Diseases / metabolism
  • Autoimmune Diseases / pathology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / metabolism*
  • Cytokines / metabolism*
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Glomerulonephritis, Membranous / immunology*
  • Glomerulonephritis, Membranous / metabolism
  • Glomerulonephritis, Membranous / pathology
  • Humans
  • Immunohistochemistry
  • Male
  • Rats
  • Rats, Inbred Lew
  • Rats, Sprague-Dawley
  • Real-Time Polymerase Chain Reaction / methods
  • Receptors, Antigen, T-Cell, alpha-beta / biosynthesis
  • Receptors, Antigen, T-Cell, alpha-beta / immunology*
  • Sampling Studies
  • T-Lymphocytes / immunology
  • Vaccination / methods*

Substances

  • Autoantibodies
  • Cytokines
  • Receptors, Antigen, T-Cell, alpha-beta