Down-modulation of programmed death 1 alters regulatory T cells and promotes experimental autoimmune encephalomyelitis.
The regulatory role of programmed death 1 (PD-1) was investigated in the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Typical EAE could be induced by immunization without pertussis toxin (PTX) in PD-1-null but not in wild-type (WT) mice. However, both strains developed a similar EAE phenotype when immunized with PTX or by adoptive transfer of pathogenic T cells. In WT mice that did not develop EAE after immunization without PTX, the frequency of CD4(+)FoxP3(+) Treg cells was boosted in the periphery but not in the thymus. This increase in Treg frequency was abrogated by PD-1 deficiency or inclusion of PTX. In addition, PD-1 expression was critical to in vitro conversion of naïve myelin-specific CD4 T cells into Treg cells and was directly related to Treg suppressive activity. Finally, PD-1 was markedly down-modulated in the periphery of WT mice after administration of PTX. Therefore, down-modulation of PD-1 in Treg cells may abrogate Treg-mediated immune suppression, permitting the activation of myelin-reactive T cells and induction of EAE.
Wang
Chunhe
C
Veterans Affairs Medical Center, Portland, Oregon, USA.
Li
Yuexin
Y
Proctor
Thomas M
TM
Vandenbark
Arthur A
AA
Offner
Halina
H
D000818:Animals; D000954:Antigens, Surface / Q000235:genetics* / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D015536:Down-Regulation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D005620:Freund's Adjuvant / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D037342:Pertussis Toxin / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor; D013116:Spinal Cord / Q000473:pathology; D013194:Staining and Labeling; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D005620:Freund's Adjuvant; D037342:Pertussis Toxin