T-cell tolerance or function is determined by combinatorial costimulatory signals

EMBO J. 2006 Jun 7;25(11):2623-33. doi: 10.1038/sj.emboj.7601146. Epub 2006 May 25.


Activated in immune responses, T lymphocytes differentiate into effector cells with potent immune function. CD28 is the most prominent costimulatory receptor for T-cell activation. However, absence of CD28 costimulation did not completely impair effector function of CD4 or CD8 T cells. Moreover, increasing number of costimulatory molecules are recently found on antigen-presenting cells to regulate T-cell activation. To understand the molecular mechanisms that determine T-cell function or tolerance, we have collectively examined the roles of positive and negative costimulatory molecules. Antigen-specific naïve CD4 and CD8 T cells, only when activated in the absence of both CD28 and ICOS pathways, were completely impaired in effector function. These tolerant T cells not only were anergic with profound defects in TcR signal transduction but also completely lacked expression of effector-specific transcription factors. T-cell tolerance induction in this system requires the action by negative costimulatory molecules; T-cell proliferation and function was partially restored by inhibiting PD-1, B7-H3 or B7S1. This work demonstrates that T-cell function or tolerance is controlled by costimulatory signals.

Publication types

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

MeSH terms

  • Animals
  • Antigens, Differentiation, T-Lymphocyte / genetics
  • Antigens, Differentiation, T-Lymphocyte / immunology
  • B7-1 Antigen / genetics
  • B7-1 Antigen / immunology
  • CD28 Antigens / immunology*
  • Cells, Cultured
  • Immune Tolerance
  • Inducible T-Cell Co-Stimulator Protein
  • Interleukin-2 / immunology
  • Lymphocyte Activation*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Antigen, T-Cell / immunology
  • Signal Transduction / physiology*
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocytes / immunology*
  • Transcription, Genetic


  • Antigens, Differentiation, T-Lymphocyte
  • B7-1 Antigen
  • CD28 Antigens
  • Icos protein, mouse
  • Inducible T-Cell Co-Stimulator Protein
  • Interleukin-2
  • Receptors, Antigen, T-Cell