Acquisition of regulatory function by human CD8(+) T cells treated with anti-CD3 antibody requires TNF

Eur J Immunol. 2010 Oct;40(10):2891-901. doi: 10.1002/eji.201040485.

Abstract

Anti-CD3 mAb can modulate graft rejection and attenuate autoimmune diseases but their mechanism(s) of action remain unclear. CD8(+) T cells with regulatory function are induced in vitro by Teplizumab, a humanized anti-CD3 antibody and inhibit responses of autologous and allogeneic T cells. They inhibit CD4(+) T-cell proliferation by mechanisms involving TNF and CCL4, and by blocking target cell entry into G2/M phase of cell cycle but neither kill them, nor compete for IL-2. CD8(+) Treg can be isolated from peripheral blood following treatment of patients with Type 1 diabetes with Teplizumab, but not from untreated patients. The induction of CD8(+) Treg by anti-CD3 mAb requires TNF and signaling through the NF-κB cascade. The CD8(+) Treg express CD25, glucocorticoid-induced TNF receptor family, CTLA-4, Foxp3, and TNFR2, and the combined expression of TNFR2 and CD25 identifies a potent subpopulation of CD8(+) Treg. These studies have identified a novel mechanism of immune regulation by anti-CD3 mAb and markers that may be used to track inducible CD8(+) Treg in settings such as chronic inflammation or immune therapy.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal, Humanized
  • Antigens, CD / immunology
  • CD3 Complex / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • CTLA-4 Antigen
  • Child
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetes Mellitus, Type 1 / immunology*
  • Flow Cytometry
  • Forkhead Transcription Factors / immunology
  • Glucocorticoid-Induced TNFR-Related Protein
  • Humans
  • Interleukin-10 / immunology
  • Muromonab-CD3 / pharmacology*
  • NF-kappa B / immunology
  • Receptors, Nerve Growth Factor / immunology
  • Receptors, Tumor Necrosis Factor / immunology
  • Receptors, Tumor Necrosis Factor, Type II / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • Transforming Growth Factor beta1 / immunology
  • Tumor Necrosis Factor-alpha / immunology
  • Young Adult

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antigens, CD
  • CD3 Complex
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Glucocorticoid-Induced TNFR-Related Protein
  • Muromonab-CD3
  • NF-kappa B
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type II
  • TNFRSF18 protein, human
  • Transforming Growth Factor beta1
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • teplizumab