title: T-bet-mediated differentiation of the activated CD8+ T cell.
abstract: The T-box transcription factor, T-bet promotes the differentiation of short-lived effector CD8(+) T cells at the expense of central memory cells. How T-bet mediates these effects, and whether they are directly caused by T-bet alone are unknown, because expression of T-bet requires stimulation of the T cell by inflammatory and growth cytokines, which may have T-bet-independent functions involving T-cell differentiation. We developed an in vitro system of ectopic T-bet expression that avoids the effects of inflammatory cytokines to determine which aspects of the T-bet phenotype may be accounted for by T-bet alone. Ectopic T-bet expression by OT-I CD8(+) T cells stimulated by the H2-Kb (SIINFEKL) complex and cultured with 2 ng/mL IL-2 induced a coordinated change in gene expression leading to down-regulation of CD127 and SOCS-1 and up-regulation of CD122 and IL-15 receptor α, switching the cellular survival cytokine from IL-7 to IL-15. T-bet expression and 2 ng/mL IL-2 also led to a capacity for IFN-γ and Fas ligand expression, confirming a role in eliciting these effector functions. Finally, ectopic T-bet promoted the expression of B lymphocyte-induced maturation protein 1 by OT-I cells in the presence of 20 ng/mL IL-2, providing a mechanism for the role of T-bet in driving terminal differentiation in concert with a high level of IL-2 receptor signalling.
authors.affiliation: Wellcome Trust Immunology Unit, Department of Medicine, University of Cambridge, Medical Research Council Centre, Cambridge, UK. jjcy2@cam.ac.uk.
authors.forename: Crystal J J
authors.initials: CJ
authors.lastname: Yeo
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Fearon
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation; D053222:Fas Ligand Protein / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D019409:Interleukin-15 / Q000276:immunology / Q000378:metabolism; D053720:Interleukin-15 Receptor alpha Subunit / Q000032:analysis / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D053646:Interleukin-2 Receptor beta Subunit / Q000032:analysis / Q000276:immunology; D015851:Interleukin-7 / Q000276:immunology / Q000378:metabolism; D053699:Interleukin-7 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D000074462:Positive Regulatory Domain I-Binding Factor 1; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000276:immunology / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000276:immunology* / Q000378:metabolism; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism; D000098815:T-bet Transcription Factor
chemical_list: D053222:Fas Ligand Protein; C508022:Il2rb protein, mouse; D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D007376:Interleukin-2; D053646:Interleukin-2 Receptor beta Subunit; D015851:Interleukin-7; D053699:Interleukin-7 Receptor alpha Subunit; C513258:Prdm1 protein, mouse; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D007371:Interferon-gamma; D000074462:Positive Regulatory Domain I-Binding Factor 1