Down-modulation of programmed death 1 alters regulatory T cells and promotes experimental autoimmune encephalomyelitis

J Neurosci Res. 2010 Jan;88(1):7-15. doi: 10.1002/jnr.22181.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigens, Surface / genetics*
  • Antigens, Surface / immunology
  • Apoptosis Regulatory Proteins / genetics*
  • Apoptosis Regulatory Proteins / immunology
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Proliferation
  • Down-Regulation
  • Encephalomyelitis, Autoimmune, Experimental / genetics*
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Female
  • Flow Cytometry
  • Freund's Adjuvant / immunology
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Knockout
  • Pertussis Toxin / immunology
  • Programmed Cell Death 1 Receptor
  • Spinal Cord / pathology
  • Staining and Labeling
  • T-Lymphocytes, Regulatory / immunology*

Substances

  • Antigens, Surface
  • Apoptosis Regulatory Proteins
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Freund's Adjuvant
  • Pertussis Toxin