Critical role of CD4(+)CD25(+) regulatory T cells in preventing murine autoantibody-mediated thrombocytopenia

Exp Hematol. 2012 Apr;40(4):279-89. doi: 10.1016/j.exphem.2012.01.001. Epub 2012 Jan 10.

Abstract

Autoimmune response suppression by regulatory T cells (Tregs) helps to maintain peripheral immune tolerance, and defects in this mechanism are thought to play a role in the pathogenesis of various autoimmune diseases. In patients with immune thrombocytopenia, naturally occurring CD4(+)CD25(+) Tregs are both functionally impaired and reduced in number. This study was undertaken to investigate Tregs' role in preventing immune thrombocytopenia in mice. Treg-deficient mice were prepared by inoculation of Treg-depleted CD4(+)CD25(-) T cells isolated from BALB/c mice into syngeneic nude mice intravenously. Platelet count, proportion of reticulated platelets, platelet-associated IgG, platelet-associated anti-platelet antibodies, and IgG anti-platelet antibody production in splenocyte cultures were examined by flow cytometry. Of 69 Treg-deficient mice, 25 (36%) spontaneously developed thrombocytopenia that lasted at least 5 weeks. The platelet-associated IgG level and proportion of reticulated platelets were elevated in the thrombocytopenic mice. Platelet eluates and splenocyte culture supernatants prepared from thrombocytopenic mice, but not from nonthrombocytopenic mice, contained IgG antibodies capable of binding to intact platelets. Simultaneous transfer of Tregs completely prevented the onset of thrombocytopenia, but Treg transfer after the onset of thrombocytopenia had no apparent effect. Treatment with IgG anti-cytotoxic T lymphocyte-associated antigen 4 antibody canceled this Treg-governed suppressive effect. In summary, these results indicate that Tregs play a critical role in preventing murine autoantibody-mediated thrombocytopenia by engaging cytotoxic T lymphocyte-associated antigen 4.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantibodies / immunology
  • Blood Platelets / immunology
  • Blood Platelets / ultrastructure
  • CD4-Positive T-Lymphocytes / transplantation
  • Cells, Cultured / immunology
  • Culture Media, Conditioned
  • Disease Models, Animal
  • Female
  • Immunoglobulin G / immunology
  • Immunotherapy, Adoptive
  • Interleukin-2 Receptor alpha Subunit / analysis
  • Lymphocyte Depletion
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Parietal Cells, Gastric / immunology
  • Platelet Glycoprotein GPIIb-IIIa Complex / immunology
  • Purpura, Thrombocytopenic, Idiopathic / etiology
  • Purpura, Thrombocytopenic, Idiopathic / immunology
  • Purpura, Thrombocytopenic, Idiopathic / prevention & control*
  • Purpura, Thrombocytopenic, Idiopathic / therapy
  • Self Tolerance
  • Spleen / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / transplantation
  • Transplantation, Isogeneic

Substances

  • Autoantibodies
  • Culture Media, Conditioned
  • Immunoglobulin G
  • Interleukin-2 Receptor alpha Subunit
  • Platelet Glycoprotein GPIIb-IIIa Complex