Effects of IL-7 on Early Human Thymocyte Progenitor Cells In Vitro and in SCID-hu Thy/Liv Mice (original) (raw)
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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.
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.
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.
Interleukin-7 is a critical growth factor in early human T-cell development
Blood, 1996
Highly purified human CD34+ fetal liver stem cells differentiate to mature T cells when seeded in vitro into isolated fetal thymic lobes of severe combined immunodeficient (SCID) mice followed by fetal thymus organ culture (FTOC). Here, this chimeric human-mouse FTOC was used to address the role of interleukin-7 (IL-7) and of the alpha chain of the IL-7 receptor (IL-7R alpha) in early human T-cell development. We report that addition of either the monoclonal antibody (MoAb) M25, which neutralizes both human and mouse IL-7, or the MoAb M21, which recognizes and blocks exclusively the human high-affinity alpha-chain of the IL-7R, results in a profound reduction in human thymic cellularity. Analysis of lymphoid subpopulations indicates that a highly reduced number of cells undergo maturation from CD34+ precursor cells toward CD4+CD3-CD1+ progenitor cells and subsequently toward CD4+CD8+ thymocytes. Our results reveal a critical role for IL-7 during early human thymocyte development, an...
BMC Immunology, 2012
Background: The role of IL-7 and pre-TCR signaling during T cell development has been well characterized in murine but not in human system. We and others have reported that human BM hematopoietic progenitor cells (HPCs) display poor proliferation, inefficient double negative (DN) to double positive (DP) transition and no functional maturation in the in vitro OP9-Delta-like 1 (DL1) culture system. Results: In this study, we investigated the importance of optimal IL-7 and pre-TCR signaling during adult human T cell development. Using a modified OP9-DL1 culture ectopically expressing IL-7 and Fms-like tyrosine kinase 3 ligand (Flt3L), we demonstrated enhanced T cell precursor expansion. IL-7 removal at various time points during T cell development promoted a slight increase of DP cells; however, these cells did not differentiate further and underwent cell death. As pre-TCR signaling rescues DN cells from programmed cell death, we treated the culture with anti-CD3 antibody. Upon pre-TCR stimulation, the IL-7 deprived T precursors differentiated into CD3 + TCRαβ + DP cells and further matured into functional CD4 T cells, albeit displayed a skewed TCR Vβ repertoire. Conclusions: Our study establishes for the first time a critical control for differentiation and maturation of adult human T cells from HPCs by concomitant regulation of IL-7 and pre-TCR signaling.
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...