TCR stimulation with modified anti-CD3 mAb expands CD8+ T cell population and induces CD8+CD25+ Tregs

J Clin Invest. 2005 Oct;115(10):2904-13. doi: 10.1172/JCI23961. Epub 2005 Sep 15.


Modified anti-CD3 mAbs are emerging as a possible means of inducing immunologic tolerance in settings including transplantation and autoimmunity such as in type 1 diabetes. In a trial of a modified anti-CD3 mAb [hOKT3gamma1(Ala-Ala)] in patients with type 1 diabetes, we identified clinical responders by an increase in the number of peripheral blood CD8+ cells following treatment with the mAb. Here we show that the anti-CD3 mAb caused activation of CD8+ T cells that was similar in vitro and in vivo and induced regulatory CD8+CD25+ T cells. These cells inhibited the responses of CD4+ cells to the mAb itself and to antigen. The regulatory CD8+CD25+ cells were CTLA4 and Foxp3 and required contact for inhibition. Foxp3 was also induced on CD8+ T cells in patients during mAb treatment, which suggests a potential mechanism of the anti-CD3 mAb immune modulatory effects involving induction of a subset of regulatory CD8+ T cells.

Publication types

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

MeSH terms

  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology*
  • Antigens, CD
  • Antigens, Differentiation / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • CTLA-4 Antigen
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetes Mellitus, Type 1 / immunology
  • Dose-Response Relationship, Immunologic
  • Forkhead Transcription Factors / immunology
  • Humans
  • Immunosuppressive Agents / immunology
  • Immunosuppressive Agents / pharmacology*
  • Lymphocyte Activation / drug effects
  • Muromonab-CD3 / immunology
  • Muromonab-CD3 / pharmacology*
  • Receptors, Interleukin-2 / immunology*
  • Transplantation
  • Transplantation Tolerance / drug effects
  • Transplantation Tolerance / immunology


  • Antibodies, Monoclonal
  • Antigens, CD
  • Antigens, Differentiation
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Immunosuppressive Agents
  • Muromonab-CD3
  • Receptors, Interleukin-2