New insights into IL-7 signaling pathways during early and late T cell development (original) (raw)
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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.
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...
Role of the Intracellular Domain of IL-7 Receptor in T Cell Development
The Journal of Immunology, 2007
Signals from the IL-7R are uniquely required for T cell development and maintenance, despite the resemblance of IL-7R to other cytokine receptors and the apparent sharing of common signaling pathways. This unique requirement could either reflect unique expression of IL-7R or IL-7, or it could indicate that the IL-7R delivers unique signals. To determine whether the IL-7R provided unique signals, we exchanged its intracellular domain with that of other cytokine receptors: IL-4R, IL-9R, and prolactin receptor (PRLR). Chimeric receptors were used to reconstitute development of IL-7R ؊/؊ hemopoietic progenitors by transducing the receptors in retroviral vectors. Whereas IL-7R ؊/؊ thymocytes are arrested at the double-negative stage, IL-4R, IL-9R, or PRLR all imparted some progression to the double-positive stage. IL-4R and PRLR gave only small numbers of thymocytes, whereas IL-9R gave robust ␣ T cell development and reconstitution of peripheral CD4 and CD8 cells, indicating that it can duplicate many of the functions of IL-7R. However, IL-9R failed to reconstitute rearrangement of the TCR␥ locus or development of ␥␦ T cells. Thus, the IL-7R signals required in the ␣ T cell lineage (such as survival and proliferation) are not unique to this receptor, whereas rearrangement of the TCR␥ locus may require a signal that is not shared by other receptors.
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.
Immunology, 1997
In this report we have studied the influence of interleukin-7 (IL-7) on thymocyte differentiation by evaluating the effects of IL-7 on the generation of T-cell receptor-ap (TCR-ac4) and TCR-'y6 thymocyte subpopulations in rat fetal thymus organ culture. IL-7 enhanced the differentiation pathway of TCRac4 thymocytes, first increasing the numbers of immature CD8+ cells, and later those of both CD4+CD8+ and mature thymocytes. The kinetics of thymocyte migration out of thymic lobes was also accelerated, and the average number of mature TCRC43hi emigrants per day was increased in the presence of IL-7. Moreover, mature CD4-CD8+ thymocytes were preferentially generated after IL-7 administration. This TCR-c4h1 cell population was not actively dividing, indicating that IL-7-promoted thymocyte differentiation was selective to the CD8 cell lineage. Distribution of some TCR-Vac and TCR-V,3 segments among mature thymocytes was also modified in IL-7-treated thymic lobes. On the contrary, the maturation of TCR-y6 was not affected by IL-7 addition during the first days of culture, but their numbers sharply increased by day 6 of culture. These results were confirmed with IL-7-treated cultures for 24 hr, showing that IL-7 responsiveness was acquired by TCR-'y6 cells late in thymus ontogeny. The present results thus indicate a key role for IL-7 in the maturation of TCR-acp thymocytes and the expansion of thymic TCR-'y8 cells.
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.
Journal of Experimental Medicine, 2004
Intrathymic T cell development depends on signals transduced by both T cell receptor and cytokine receptors. Early CD4 Ϫ CD8 Ϫ (double negative) thymocytes require interleukin (IL)-7 receptor (IL-7R) signals for survival and proliferation, but IL-7R signals are normally extinguished by the immature single positive (ISP) stage of thymocyte development. We now demonstrate that IL-7R signals inhibit expression of transcription factors TCF-1, LEF-1, and ROR ␥ t that are required for the ISP to double positive (DP) transition in the thymus. In addition, we demonstrate that IL-7R signals also inhibit TCF-1 and LEF-1 expression in mature peripheral T cells. Thus, the present work has identified several important downstream target genes of IL-7R signaling in T cells and thymocytes that provide a molecular mechanism for the inhibitory influence of IL-7R signaling on DP thymocyte development. We conclude that IL-7R signals down-regulate transcription factors required for the ISP to DP transition and so must be terminated by the ISP stage of thymocyte development.
Development of regulatory T cells requires IL-7R stimulation by IL-7 or TSLP
Blood, 2008
Interleukin-7 (IL-7), a cytokine produced by stromal cells, is required for thymic development and peripheral homeostasis of most major subsets of T cells. We examined whether regulatory T (Treg) cells also required the IL-7 pathway by analyzing IL-7Ralpha(-/-) mice. We observed a striking reduction in cells with the Treg surface phenotype (CD4, CD25, GITR (glucocorticoid-induced tumor necrosis factor [TNF]-like receptor), CD45RB, CD62L, CD103) or intracellular markers (cytotoxic T-lymphocyte-associated antigen-4, CTLA-4, and forkhead box transcription factor 3, Foxp3). Foxp3 transcripts were virtually absent in IL-7Ralpha(-/-) lymphoid tissues, and no Treg cell suppressive activity could be detected. There are 2 known ligands for IL-7Ralpha: IL-7 itself and thymic stromal lymphopoietin (TSLP). Surprisingly, mice deficient in IL-7 or the other chain of the TSLP receptor (TSLPR) developed relatively normal numbers of Treg cells. Combined deletion of IL-7 and TSLP receptor greatly reduced Treg cell development in the thymus but was not required for survival of mature peripheral Treg cells. We conclude that Treg cells, like other T cells, require signals from the IL-7 receptor, but unlike other T cells, do not require IL-7 itself because of at least partially overlapping actions of IL-7 and TSLP for development of Treg cells.
The Journal of Immunology, 2009
By coculturing human postnatal thymus hematopoietic progenitors and OP9-huDL1 stromal cells, we found that murine IL-7 is ϳ100-fold less potent than human IL-7 for supporting human T cell development in vitro. We investigated the role of human IL-7 in newborn BALB/c Rag2 ؊/؊ ␥ c ؊/؊ mice transplanted with human hematopoietic stem cells (HSC) as an in vivo model of human hematopoiesis using three approaches to improve IL-7 signaling: administration of human IL-7, ectopic expression of human IL-7 by the transplanted human HSC, or enforced expression of a murine/human chimeric IL-7 receptor binding murine IL-7. We show that premature IL-7 signaling at the HSC stage, before entrance in the thymus, impeded T cell development, whereas increased intrathymic IL-7 signaling significantly enhanced the maintenance of immature thymocytes. Increased thymopoiesis was also observed when we transplanted BCL-2-or BCL-x L -transduced human HSC. Homeostasis of peripheral mature T cells in this humanized mouse model was not improved by any of these strategies. Overall, our results provide evidence for an important role of IL-7 in human T cell development in vivo and highlight the notion that IL-7 availability is but one of many signals that condition peripheral T cell homeostasis.