IL-7 enhances thymic human T cell development in "human immune system" Rag2-/-IL-2Rgammac-/- mice without affecting peripheral T cell homeostasis.
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 approximately 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(-/-)gamma(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.
van Lent
Anja U
AU
Department of Cell Biology and Histology, Center for Immunology of Amsterdam, Academic Medical Center of the University of Amsterdam, The Netherlands.
Dontje
Wendy
W
Nagasawa
Maho
M
Siamari
Rachida
R
Bakker
Arjen Q
AQ
Pouw
Stephan M
SM
Maijoor
Kelly A
KA
Weijer
Kees
K
Cornelissen
Jan J
JJ
Blom
Bianca
B
Di Santo
James P
JP
Spits
Hergen
H
Legrand
Nicolas
N
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics*; D015851:Interleukin-7 / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D050506:Mutant Chimeric Proteins / Q000172:deficiency / Q000235:genetics; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
D004268:DNA-Binding Proteins; C508605:IL7 protein, human; D053631:Interleukin Receptor Common gamma Subunit; D015851:Interleukin-7; D050506:Mutant Chimeric Proteins; D009687:Nuclear Proteins; C499311:RAG2 protein, human