IL-7 Enhances Thymic Human T Cell Development in “Human Immune System” Rag2−/−IL-2Rγc−/− Mice without Affecting Peripheral T Cell Homeostasis

• Published in: The Journal of immunology (1950) 2009-12, Vol.183 (12), p.7645-7655
• Main Authors: van Lent, Anja U., Dontje, Wendy, Nagasawa, Maho, Siamari, Rachida, Bakker, Arjen Q., Pouw, Stephan M., Maijoor, Kelly A., Weijer, Kees, Cornelissen, Jan J., Blom, Bianca, Di Santo, James P., Spits, Hergen, Legrand, Nicolas
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0902019

IL-7 is a central cytokine in the development of hematopoietic cells, although interspecies discrepancies have been reported. By coculturing human postnatal thymus hematopoietic progenitors and OP9-huDL1 stromal cells, we found that murine IL-7 is ∼100-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−/−γc−/− 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-xL-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.