Thymocyte Development: Cytokines Have the Casting Vote

ReseaRch highlights

Nature Reviews Immunology | AOP, published online 19 February 2010; doi:10.1038/nri2732

tHymOCytE dEvELOPmENt Cytokines have the casting vote

Signals through the T cell receptor other STAT molecules. The authors the TCR-associated tyrosine kinase (TCR) are crucial for the positive conclude that STAT-mediated ZAP70 were crossed with Socs1- selection of double-positive (DP) cytokine signalling is required for the knockout mice transgenic for the IL-7 thymocytes and for the differen- generation of most, if not all, CD8+ receptor α-chain to produce mice in tiation of CD4+ T cells. Far less thymocytes, which was supported by which thymocytes were arrested at a is known about how CD8+ T cell the total lack of CD8+ thymocytes in pre-selection DP stage, owing to a lack lineage specification occurs; this mice transgenic for the STAT signal- of TCR signalling, but were responsive study indicates that although TCR ling inhibitor suppressor of cytokine to IL-7. In vitro culture of purified DP signalling sets the stage for the differ- signalling 1 (SOCS1). thymocytes from these mice with IL-7 entiation of CD8+ T cells, signalling In an in vitro model of positive or transgenic intrathymic expression by cytokines such as interleukin-7 selection, the Runt-family transcrip- of IL-7 in vivo resulted in RUNX3 (IL-7) is the deciding factor. tion factor RUNX3 — which speci- expression by thymocytes and the dif- TCR-mediated positive selection fies the CD8+ T cell lineage — was ferentiation of CD8+ T cells expressing converts cytokine-unresponsive DP expressed only after stimulation markers of functional competence. thymocytes into cytokine-responsive with IL-7 and required signalling These data support a model of intermediate thymocytes, the dif- through STAT5 and/or STAT6. CD8+ lineage specification that ferentiation of which into CD4+ Transgenic expression of RUNX3 depends on cytokine signalling but or CD8+ cells was thought to be partially restored the generation of for which TCR signalling is dispen- determined by the duration of TCR CD8+ thymocytes in Socs1-transgenic sable. The authors found that TCR signalling. The authors looked at the (cytokine-unresponsive) mice. signalling induces the expression of role of IL-7, the main cytokine to These results indicate that RUNX3 CC-chemokine receptor 7 (CCR7) be expressed in the thymus, in this is expressed downstream of cytokine by thymocytes, which promotes process using mice with a conditional signalling and can induce a CD8+ their migration from the cortex to deletion of signal transducer and thymocyte fate in the absence the cytokine-rich medulla, where activator of transcription 5a (Stat5a) of cytokine signalling. However, they receive the necessary cytokine and Stat5b in thymo cytes from the transgenic expression of RUNX3 stimulation for RUNX3 expression DP stage onwards. These mice had did not fully restore CD8+ thymocyte and differentiation to CD8+ T cells. normal numbers of CD4+ thymocytes numbers, which shows that cytokine Kirsty Minton but a 50% lower frequency of CD8+ signalling might have other important ORIGINAL RESEARCH PAPER Park, J.-H. et al. thymocytes than wild-type mice. Mice effects on these cells. Signaling by intrathymic cytokines, not T cell deficient for both STAT5 and STAT6 So, can cytokine signalling induce antigen receptors, specifies CD8 lineage choice had 85% fewer CD8+ thymocytes, CD8+ thymocyte differentiation and promotes the differentiation of cytotoxic- lineage T cells. Nature Immunol. 31 Jan 2010 which indicates that in the absence in the absence of TCR-mediated (doi:10.1038/ni.1840) of STAT5, IL-7 might signal through positive selection? Mice deficient for