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  • The EMBO Journal (2006) 25, 2623 - 2633
  • doi:10.1038/sj.emboj.7601146

Published online: 25 May 2006

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

Roza Nurieva1, Sunil Thomas2,a, Thang Nguyen2,a, Natalia Martin-Orozco1, Ying Wang2, Murali-Krishna Kaja2, Xue-Zhong Yu3 and Chen Dong1

  1. Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
  2. Department of Immunology, University of Washington, Seattle, WA, USA
  3. H Lee Moffitt Cancer Center & Research Institute, University of South Florida, Tampa, FL, USA

Correspondence to:

Chen Dong, Department of Immunology, University of Texas MD Anderson Cancer Center, 7455 Fannin, Unit 906, Houston, TX 77030, USA. Tel.: +1 713 563 3203; Fax: +1 713 563 0604; E-mail: cdong@mdanderson.org

aThese authors contributed equally to this study

Received 9 December 2005; Accepted 24 April 2006

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.

  • Keywords:

    • costimulation,
    • differentiation,
    • IL-2,
    • T cells,
    • tolerance