Anti-programmed cell death 1 antibody reduces CD4+PD-1+ T cells and relieves the lupus-like nephritis of NZB/W F1 mice.
Programmed cell death 1 (PD-1) is an immunosuppressive receptor that transduces an inhibitory signal into activated T cells. Although a single nucleotide polymorphism in the gene for PD-1 is associated with susceptibility to systemic lupus erythematosus, the role of PD-1 in systemic lupus erythematosus is still not well understood. In this study, we used NZB/W F1 mice, a model of lupus-like nephritis, to examine the function of PD-1 and its ligands. PD-1 was predominantly expressed on CD4(+) T cells that infiltrated the kidney, and CD4(+)PD-1(high) T cells produced higher levels of IFN-gamma than CD4(+)PD-1(low) or CD4(+)PD-1(-) T cells. Stimulation with PMA/ionomycin caused splenic CD4(+)PD-1(+) T cells to secrete high levels of IFN-gamma, IL-10, low levels of TNF-alpha, faint levels of IL-2, IL-21, and no IL-4, IL-17. In vivo anti-PD-1 mAb treatment reduced the number of CD4(+)PD-1(+) T cells in the kidney of NZB/W F1 mice and significantly reduced their mortality rate (p = 0.03). Conversely, blocking PD-L1 using an anti-PD-L1 mAb increased the number of CD4(+)PD-1(+) T cells in the kidney, enhanced serum IFN-gamma, IL-10, and IgG2a ds-DNA-Ab levels, accelerated the nephritis, and increased the mortality rate. We conclude that CD4(+)PD-1(high) T cells are dysregulated IFN-gamma-producing, proinflammatory cells in NZB/W F1 mice.
Department of Clinical Pathology and Immunology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
Shimpei
S
Kasagi
Seiji
S
Kawano
Taku
T
Okazaki
Tasuku
T
Honjo
Akio
A
Morinobu
Saori
S
Hatachi
Kenichiro
K
Shimatani
Yoshimasa
Y
Tanaka
Nagahiro
N
Minato
Shunichi
S
Kumagai
D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000943:Antigens, Differentiation / Q000276:immunology / Q000378:metabolism*; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D060890:B7-H1 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000097:blood; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009393:Nephritis / Q000378:metabolism* / Q000401:mortality / Q000517:prevention & control; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma