CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2

Nat Immunol. 2005 Feb;6(2):152-62. doi: 10.1038/ni1160. Epub 2005 Jan 9.


Efficient generation of regulatory T cells (T(reg) cells) in the thymus requires CD28 costimulation, but it is not known why. Here, molecular mapping of CD28 costimulation showed that T(reg) cell generation requires a motif that binds the tyrosine kinase Lck, precisely the same motif that is required for CD28 costimulation of interleukin 2 production. Nevertheless, CD28 costimulation provides more than interleukin 2 to developing T(reg) cells, as CD28 costimulation of T cell receptor-signaled double-positive thymocytes induced expression of Foxp3, considered to be the T(reg) 'master gene', as well as GITR and CTLA-4, two proteins expressed on T(reg) cells. Thus, CD28 costimulation directly signals developing thymocytes to express Foxp3 and to initiate the T(reg) cell differentiation program.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CD28 Antigens / chemistry
  • CD28 Antigens / genetics
  • CD28 Antigens / immunology
  • CD28 Antigens / metabolism*
  • Cell Differentiation*
  • DNA-Binding Proteins / metabolism*
  • Forkhead Transcription Factors
  • Interleukin-2 / biosynthesis
  • Interleukin-2 / immunology*
  • Interleukin-2 / metabolism
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*
  • Thymus Gland / cytology*
  • Thymus Gland / immunology
  • Thymus Gland / metabolism


  • CD28 Antigens
  • DNA-Binding Proteins
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-2