Tolerogenic treatment of lupus mice with consensus peptide induces Foxp3-expressing, apoptosis-resistant, TGFbeta-secreting CD8+ T cell suppressors.
Lupus-prone (NZB x NZW)F1 mice spontaneously develop elevated titers of anti-DNA Abs that contain T cell determinants in their V(H) regions. We have previously shown that tolerization with an artificial peptide based on these T cell determinants (pConsensus (pCons)) can block production of anti-DNA Abs and prolong survival of the mice. In this study, we show that this protection depends in part on the generation of peripheral TGFbeta- and Foxp3-expressing inhibitory CD8+ (Ti) cells. These CD8+ Ti cells suppress anti-DNA IgG production both in vitro and in vivo and require up-regulated expression of both Foxp3 and TGFbeta to exert their suppressive function, as indicated by microarray analyses, small interfering RNA inhibition studies, and blocking experiments. Additionally, CD8+ Ti cells from pCons-tolerized mice were longer-lived suppressors that up-regulated expression of Bcl-2 and were more resistant to apoptosis than similar cells from naive mice. These data indicate that clinical suppression of autoimmunity after administration of pCons depends in part on the generation of CD8+ Ti cells that suppress secretion of anti-DNA Ig using mechanisms that include Foxp3, TGFbeta, and resistance to apoptosis.
Hahn
Bevra H
BH
Department of Medicine, Division of Rheumatology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. bhahn@mednet.ucla.edu
Singh
Ram Pyare
RP
La Cava
Antonio
A
Ebling
Fanny M
FM
D019264:Adoptive Transfer; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis / Q000276:immunology; D017209:Apoptosis / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007135:Immunoglobulin Variable Region / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000517:prevention & control*; D051379:Mice; D008814:Mice, Inbred NZB; D046228:Microarray Analysis; D009842:Oligopeptides / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000276:immunology
D000974:Antibodies, Antinuclear; C106243:CP-1 peptide; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007135:Immunoglobulin Variable Region; D009842:Oligopeptides; D016212:Transforming Growth Factor beta