title: Signaling by intrathymic cytokines, not T cell antigen receptors, specifies CD8 lineage choice and promotes the differentiation of cytotoxic-lineage T cells.
abstract: Immature CD4(+)CD8(+) (double-positive (DP)) thymocytes are signaled via T cell antigen receptors (TCRs) to undergo positive selection and become responsive to intrathymic cytokines such as interleukin 7 (IL-7). We report here that cytokine signaling is required for positively selected thymocytes to express the transcription factor Runx3, specify CD8 lineage choice and differentiate into cytotoxic-lineage T cells. In DP thymocytes genetically engineered to be cytokine responsive, IL-7 signaling induced TCR-unsignaled DP thymocytes to express Runx3 and to differentiate into mature CD8(+) T cells, completely circumventing positive selection. We conclude that TCR-mediated positive selection converts DP cells into cytokine-responsive thymocytes, but it is subsequent signaling by intrathymic cytokines that specifies CD8 lineage choice and promotes differentiation into cytotoxic-lineage T cells.
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Park
authors.forename: Stanley
authors.initials: S
authors.lastname: Adoro
authors.forename: Terry
authors.initials: T
authors.lastname: Guinter
authors.forename: Batu
authors.initials: B
authors.lastname: Erman
authors.forename: Amala S
authors.initials: AS
authors.lastname: Alag
authors.forename: Marta
authors.initials: M
authors.lastname: Catalfamo
authors.forename: Motoko Y
authors.initials: MY
authors.lastname: Kimura
authors.forename: Yongzhi
authors.initials: Y
authors.lastname: Cui
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Lucas
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Gress
authors.forename: Masato
authors.initials: M
authors.lastname: Kubo
authors.forename: Lothar
authors.initials: L
authors.lastname: Hennighausen
authors.forename: Lionel
authors.initials: L
authors.lastname: Feigenbaum
authors.forename: Alfred
authors.initials: A
authors.lastname: Singer
mesh_terms: D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage; D050677:Core Binding Factor Alpha 3 Subunit / Q000276:immunology; D016207:Cytokines / Q000276:immunology*; D005434:Flow Cytometry; D015851:Interleukin-7 / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050799:STAT5 Transcription Factor / Q000276:immunology; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D050677:Core Binding Factor Alpha 3 Subunit; D016207:Cytokines; D015851:Interleukin-7; C493730:Runx3 protein, mouse; D050799:STAT5 Transcription Factor