Signaling by intrathymic cytokines, not T cell antigen receptors, specifies CD8 lineage choice and promotes the differentiation of cytotoxic-lineage T cells.
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.
Park
Jung-Hyun
JH
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Adoro
Stanley
S
Guinter
Terry
T
Erman
Batu
B
Alag
Amala S
AS
Catalfamo
Marta
M
Kimura
Motoko Y
MY
Cui
Yongzhi
Y
Lucas
Philip J
PJ
Gress
Ronald E
RE
Kubo
Masato
M
Hennighausen
Lothar
L
Feigenbaum
Lionel
L
Singer
Alfred
A
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*
D050677:Core Binding Factor Alpha 3 Subunit; D016207:Cytokines; D015851:Interleukin-7; C493730:Runx3 protein, mouse; D050799:STAT5 Transcription Factor