Control of T Cell Development In Vivo by Subdomains Within the IL-7 Receptor α-Chain Cytoplasmic Tail

IL-7 and IL-15 play important roles in γδ T cell development. These receptors transmit proliferation and/or survival signals in γδ T cells. In addition, the IL-7R promotes recombination and transcription in the TCR γ locus. To clarify the role of the cytokine receptors in the development of epidermal γδ T cells, we introduced a Vγ3/Vδ1 TCR transgene, derived from Thy-1+ dendritic epidermal T cells (DETC), into IL-7Rα-deficient mice, and we found that they partly rescued γδ T cells in the adult thymus but not in the spleen. Introduction of an additional Bcl-2 transgene had a minimal effect on γδ T cells in the adult thymus of these mice. In contrast to the adult thymus, the introduction of the Vγ3/Vδ1 TCR transgene into IL-7Rα−/− mice completely restored Vγ3+ T cells in the fetal thymus and DETC in the adult skin. On the contrary, the same Vγ3/Vδ1 TCR transgene failed to rescue DETC in the skin of IL-2Rβ-deficient mice, even with the additional Bcl-2 transgene. These results suggest that the IL-2/IL-15R, rather than the IL-7R, plays an essential role in proliferation and survival of DETC in the fetal thymus and the skin. In contrast, the IL-7R is probably essential in the induction of V-J recombination of TCRγ genes. Thus, this study proves that IL-7R and IL-2/IL-15R serve differential functions in epidermal γδ T cell development.

Section: Discussionmentioning

confidence: 99%

Differential Roles of Cytokine Receptors in the Development of Epidermal γδ T Cells

Maki

Lee

et al. 2001

“…Furthermore, IL-7-mediated signals promote the differentiation and maintain the viability of CD4-CD8 ϩ thymocytes (39). The paucity of IL-7-expressing TECs in the cortex corresponds to the lack of IL-7R expression on DP cortical thymocytes (54). In the absence of IL-7 signaling, nonselected DP thymocytes down-regulate bcl-2 expression and undergo apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Ontogeny and Regulation of IL-7-Expressing Thymic Epithelial Cells

Zamisch

Moore-Scott²,

Su³

et al. 2005

115

Epithelial cells in the thymus produce IL-7, an essential cytokine that promotes the survival, differentiation, and proliferation of thymocytes. We identified IL-7-expressing thymic epithelial cells (TECs) throughout ontogeny and in the adult mouse thymus by in situ hybridization analysis. IL-7 expression is initiated in the thymic fated domain of the early primordium by embryonic day 11.5 and is expressed in a Foxn1-independent pathway. Marked changes occur in the localization and regulation of IL-7-expressing TECs during development. IL-7-expressing TECs are present throughout the early thymic rudiment. In contrast, a major population of IL-7-expressing TECs is localized to the medulla in the adult thymus. Using mouse strains in which thymocyte development is arrested at various stages, we show that fetal and postnatal thymi differ in the frequency and localization of IL-7-expressing TECs. Whereas IL-7 expression is initiated independently of hemopoietic-derived signals during thymic organogenesis, thymocyte-derived signals play an essential role in regulating IL-7 expression in the adult TEC compartment. Moreover, different thymocyte subsets regulate the expression of IL-7 and keratin 5 in adult cortical epithelium, suggesting that despite phenotypic similarities, the cortical TEC compartments of wild-type and RAG-1−/− mice are developmentally and functionally distinct.

“…Among them, Tyr 449 plays a crucial role in proliferation and survival of lymphocyte precursors by triggering STAT5 and PI3K activation (6,7). However, there are conflicting reports as to whether the Tyr 449 is required for TCR␥ recombination and ␥␦ T cell development (14,24). Recently, it was reported that IL-7R␣-Phe 449 knock-in mice exhibit reduced but detectable levels of ␥␦ T cells (25).…”

mentioning

confidence: 99%

MEK1/2 Induces STAT5-Mediated Germline Transcription of the TCRγ Locus in Response to IL-7R Signaling

Maki

Ikuta

2008

The IL-7R plays an essential role in γδ T cell development by inducing V-J recombination of the TCRγ locus through STAT5. Although tyrosine residues in the intracellular domain of the mouse IL-7R α-chain (IL-7Rα) have been implicated in STAT5 activation, it is still unknown whether they are essential for γδ T cell development. In this study, we showed that those IL-7Rα tyrosine residues are not essential for γδ T cell development, because phenylalanine replacement of four intracellular tyrosine residues (IL-7R-FFFF) partially rescued γδ T cell development of IL-7Rα−/− progenitors. To examine signaling pathways activated by IL-7R-FFFF, we introduced a chimeric receptor consisting of the human IL-4R α-chain and mouse IL-7R-FFFF (4R/7R-FFFF) into an IL-7-dependent pre-B cell line and found that 4R/7R-FFFF induced TCRγ germline transcription and STAT5 activation. Treatment of cells with MEK1/2 inhibitors significantly decreased levels of TCRγ germline transcription and STAT5 tyrosine phosphorylation mediated by 4R/7R-FFFF, suggesting that MEK1/2 plays an alternative role in STAT5 activation by IL-7R. MEK1/2 associated with STAT5 and induced STAT5 tyrosine phosphorylation and DNA binding activity. Furthermore, MEK1 directly phosphorylated a STAT5 tyrosine residue in vitro. Finally, active MEK1 partially rescued TCRγ germline transcription by IL-7R in a pre-T cell line. These results demonstrate that MEK1/2 induces TCRγ germline transcription by phosphorylating STAT5 through IL-7R-FFFF and suggest a potential role for MAPK in IL-7R tyrosine-independent activation of STAT5.