title: T-cell tolerance or function is determined by combinatorial costimulatory signals.
abstract: 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.
authors.affiliation: Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Roza
authors.initials: R
authors.lastname: Nurieva
authors.forename: Sunil
authors.initials: S
authors.lastname: Thomas
authors.forename: Thang
authors.initials: T
authors.lastname: Nguyen
authors.forename: Natalia
authors.initials: N
authors.lastname: Martin-Orozco
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Murali-Krishna
authors.initials: MK
authors.lastname: Kaja
authors.forename: Xue-Zhong
authors.initials: XZ
authors.lastname: Yu
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
mesh_terms: D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology*; D002478:Cells, Cultured; D007108:Immune Tolerance; D060889:Inducible T-Cell Co-Stimulator Protein; D007376:Interleukin-2 / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014158:Transcription, Genetic
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D018122:B7-1 Antigen; D018106:CD28 Antigens; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell