IL-7 Receptor Signals Inhibit Expression of Transcription Factors TCF-1, LEF-1, and ROR t: Impact on Thymocyte Development (original) (raw)
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European Journal of Immunology, 2003
The pre-T cell receptor (pre-TCR) and IL-7 receptor (IL-7R) are critical mediators of survival, proliferation and differentiation in immature thymocytes. Here we show that pre-TCR signaling directly maintains IL-7Rα expression as developing thymocytes undergo β-selection. Inhibition of IL-7/IL-7R signaling in (CD44–CD25–) DN4 cells results in decreased generation of double-positive thymocytes due to increased death of rapidly proliferating β-selected cells. Thus, we identify a mechanism by which pre-TCR signaling controls the selective survival of TCRβ+ thymocytes, and define a further stage of T cell differentiation in which signaling from a TCR regulates the ability of that cell to respond to cytokine.
Dynamic regulation of IL-7 receptor expression is required for normal thymopoiesis
Blood, 2004
IL-7 receptor (IL-7R) levels are tightly controlled during ontogeny: high on DN cells, absent on DP cells, and high once again on thymocytes undergoing positive selection. To determine if loss of IL-7-mediated survival signals in DP cells is necessary for normal antigen-specific selection, we created T-lineage specific IL-7R α chain (IL-7Rα) transgenic (Tg) mice in which IL-7R is expressed throughout ontogeny. There was no effect of the IL-7Rα Tg on negative selection. Surprisingly, however, although the thymi of IL-7Rα Tg mice were comparable at birth, there was a decrease in thymocyte number as the mice aged. This was found to be due to competition between DN and IL-7Rexpressing DP cells for endogenous IL-7, which resulted in decreased levels of Bcl-2 in DN cells, increased DN apoptosis, and decreased DN cell number. Therefore, the downregulation of IL-7R on DP cells is an "altruistic" act required for maintaining an adequate supply of local IL-7 for DN cells.
Differential IL-7 responses in developing human thymocytes
Human Immunology, 2010
IL-7 is a factor essential for mouse and human thymopoiesis. Mouse thymocytes have altered sensitivities to IL-7 at different developmental stages. CD4/CD8 double positive (DP) mouse thymocytes are shielded from the influence of IL-7 due to loss of CD127 (IL-7Rα). In this study, we assessed IL-7 receptor expression and IL-7 signaling in human thymocytes. We found human DP cells to be severely limited in their ability to phosphorylate STAT-5 in response to IL-7. The relative expression levels of the IL-7-inducible proteins Bcl-2 and Mcl-1 were also lower in human DP cells, consistent with a stage-specific decrease in IL-7 responsiveness. IL-7 responses were restored in a subset of cells that matured past the DP stage. Unlike the regulation of IL-7 signaling in mouse thymocytes, loss of IL-7 signaling in human DP cells was not due to absence of CD127 but instead correlated with downregulation of CD132 (common γ chain).
Overexpression of IL-7Rα provides a competitive advantage during early T-cell development
Blood, 2004
Critical checkpoints controlling early thymic T-cell development and homeostasis are set by the proper signaling function of the interleukin 7 receptor (IL-7R) and the pre–T-cell antigen receptor. Although αβ T-cell development is observed in IL-7– and IL-7Rα–deficient mice, the number of thymocytes is significantly reduced, implying a role for the IL-7R in controlling the size of the thymic T-cell compartment. Here, we report the overexpression of IL-7Rα that occurs in the early T-cell compartment from AKR/J mice, animals that are highly susceptible to the spontaneous development of thymoma. Increased IL-7Rα was revealed by surface staining, and increased IL-7Rα mRNA was documented by using reverse transcriptase–polymerase chain reaction (RT-PCR). This resulted in increased survival of AKR/J early thymocytes, shown by the decreased frequency of TUNEL+ (terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate [dUTP]–fluorescein nick end labeling) cells. In an in vivo...
Intrathymic IL-7: The where, when, and why of IL-7 signaling during T cell development
Seminars in Immunology, 2012
The thymus is the birthplace of all T lineage cells. But the thymus is also a cradle as it provides the environment for further maturation and differentiation of immature thymocytes. While many factors contribute to make the thymus a unique place for T cell development, here we review the essential role of intrathymic interleukin-7 (IL-7). In the absence of IL-7 signaling, survival, proliferation and differentiation of immature thymocytes are all severely impaired. Consequently, IL-7 is critical to nurture and guide T precursor cells through the diverse steps of thymic maturation. Interestingly, even as IL-7 signaling is such a critical factor, IL-7 signaling must be also actively suppressed during specific stages of T cell differentiation. These contradictory observations are puzzling but can be satisfactorily explained when understanding the developmental context of IL-7 signaling. In this regard, here we will discuss the spatiotemporal expression of intrathymic IL-7 and address the stage-specific effects of IL-7 signaling in developing thymocytes. Specifically, we will review other facets of intrathymic IL-7 beyond its role as a pro-survival factor and so clarify and reaffirm the unique role of IL-7 as a prime factor in T cell development and differentiation.
Immunology, 2013
Among the milestones that occur during T-cell development in the thymus is the expression of T-cell receptor-b (TCR-b) and the formation of the pre-TCR complex. Signals emanating from the pre-TCR trigger survival, proliferation and differentiation of T-cell precursors. Although the pre-TCR is essential for these cell outcomes, other receptors, such as Notch and CXCR4, also contribute. Whether interleukin-7 (IL-7) participates in promoting the survival or proliferation of pre-TCR-expressing cells is controversial. We used in vitro and in vivo models of T-cell development to examine the function of IL-7 in TCR-b-expressing thymocytes. Culturing TCR-b-expressing CD4 − CD8 − double-negative thymocytes in an in vitro model of T-cell development revealed that IL-7 reduced the frequency of CD4 + CD8 + double-positive thymocytes at the time of harvest. The mechanism for this change in the percentage of double-positive cells was that IL-7 promoted the survival of thymocytes that had not yet differentiated. By preserving the double-negative population, IL-7 reduced the frequency of double-positive thymocytes. Interleukin-7 was not required for proliferation in the in vitro system. To follow this observation, we examined mice lacking CD127 (IL-7Ra). In addition to the known effect of CD127 deficiency on T-cell development before TCR-b expression, CD127 deficiency also impaired the development of TCR-b-expressing double-negative thymocytes. Specifically, we found that Bcl-2 expression and cell cycle progression were reduced in TCR-b-expressing double-negative thymocytes in mice lacking CD127. We conclude that IL-7 continues to function after TCR-b is expressed by promoting the survival of TCR-b-expressing doublenegative thymocytes.
The Journal of Immunology, 2013
IL-7 is a cytokine essential for T cell development and survival. However, the local function of IL-7 produced by thymic epithelial cells (TECs) is poorly understood. To address this question, we generated IL-7-floxed mice and crossed them with FoxN1 promoter-driven Cre (FoxN1-Cre) mice to establish knockout mice conditionally deficient for the expression of IL-7 by TECs. We found that ab and gd T cells were significantly reduced in the thymus of IL-7 f/f FoxN1-Cre mice. Proportion of mature single-positive thymocytes was increased. In lymph nodes and the spleen, the numbers of T cells were partially restored in IL-7 f/f FoxN1-Cre mice. In addition, gd T cells were absent from the fetal thymus and epidermis of IL-7 f/f FoxN1-Cre mice. Furthermore, TCRgd + intraepithelial lymphocytes (IELs) were significantly decreased in the small intestines of IL-7 f/f FoxN1-Cre mice. To evaluate the function of IL-7 produced in the intestine, we crossed the IL-7 f/f mice with villin promoter-driven Cre (Vil-Cre) mice to obtain the mice deficient in IL-7 production from intestinal epithelial cells. We observed that ab and gd IELs of IL-7 f/f Vil-Cre mice were comparable to control mice. Collectively, our results suggest that TEC-derived IL-7 plays a major role in proliferation, survival, and maturation of thymocytes and is indispensable for gd T cell development. This study also demonstrates that IL-7 produced in the thymus is essential for the development of gd IELs and indicates the thymic origin of gd IELs.
Ontogeny and Regulation of IL7Expressing Thymic Epithelial Cells1
2000
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
Ontogeny and regulation of IL-7-expressing thymic epithelial cells
Journal of immunology (Baltimore, Md. : 1950), 2005
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 thy...