Blockade of programmed death-1 in young (New Zealand black x New Zealand white)F1 mice promotes the activity of suppressive CD8+ T cells that protect from lupus-like disease.
The programmed death-1 (PD-1)/programmed death-1 ligand 1 (PD-L1) pathway regulates both stimulatory and inhibitory signals. In some conditions, PD-1/PD-L1 inhibits T and B cell activation, induces anergy, and reduces cytotoxicity in CD8(+) T cells. In other conditions, PD-l/PD-L1 has costimulatory effects on T cells. We recently showed that induction of suppressive CD8(+)Foxp3(+) T cells by immune tolerance of lupus-prone (New Zealand black × New Zealand white)F(1) (BWF(1)) mice with the anti-DNA Ig-based peptide pConsensus (pCons) is associated with significantly reduced PD-1 expression on those cells. In this study, we tested directly the role of PD-1 by administering in vivo neutralizing Ab to PD-1 to premorbid BWF(1) and healthy control mice. Anti-PD-1-treated mice were protected from the onset of lupus nephritis for 10 wk, with significantly improved survival. Although the numbers of T cells declined in aging control mice, they were maintained in anti-PD-1-treated mice, including CD8(+)Foxp3(+) T cells that suppressed syngeneic CD4(+)CD25(-) T cell proliferation and IFN-γ production, reduced production of IgG and anti-dsDNA IgG, induced apoptosis in syngeneic B cells, and increased IL-2 and TGF-β production. The administration of anti-PD-1 Ab to BWF(1) mice after induction of tolerance with pCons abrogated tolerance; mice developed autoantibodies and nephritis at the same time as control mice, being unable to induce CD8(+)Foxp3(+) T suppressor cells. These data suggest that tightly regulated PD-1 expression is essential for the maintenance of immune tolerance mediated by those CD8(+)Foxp3(+) T cells that suppress both T(h) cells and pathogenic B cells. PD-1 regulation could represent a target to preserve tolerance and prevent autoimmunity.
Division of Rheumatology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095-1670, USA. maidawong@mednet.ucla.edu
Maida
M
Wong
Antonio
A
La Cava
Ram P
RP
Singh
Bevra H
BH
Hahn
D000375:Aging / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D000954:Antigens, Surface / Q000276:immunology / Q000502:physiology*; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology*; D001323:Autoantibodies / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D003433:Crosses, Genetic; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D007108:Immune Tolerance / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D061026:Programmed Cell Death 1 Receptor; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
D019138:Antibodies, Blocking; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D001323:Autoantibodies; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D016212:Transforming Growth Factor beta