title: TCR triggering modulates the responsiveness and homeostatic proliferation of CD4+ thymic emigrants to IL-7 therapy.
abstract: Interleukin-7 (IL-7) is currently used in clinical trials to augment T-cell counts. Paradoxically, elevated systemic IL-7 found in lymphopenic humans is typically insufficient for CD4(+) T-cell regeneration, and thymopoiesis becomes critical in this process. Here we show that the proliferative effect of IL-7 is more pronounced on CD4(+)CD8(-) thymocytes compared with peripheral CD4(+) T cells. These cells express miR181a at higher levels and respond to lower concentrations of IL-7. As single-positive CD4(+) thymocytes (CD4(+)(SPT)) exit the thymus, they rapidly diminish their proliferation to IL-7 therapy, and this is mediated, at least in part, by major histocompatibility complex class II distribution outside the thymus. Interestingly, increasing T-cell receptor (TCR) stimulation augments IL-7 responsiveness and proliferation of peripheral CD4(+) T cells, whereas failure to stimulate TCR abrogates proliferation induced by IL-7. Finally, we demonstrated that IL-7 enhances the proliferation of CD4(+) T cells that undergo "slow proliferation" in lymphopenic hosts. To date, our results indicate that TCR signaling is a major controlling factor for CD4 responsiveness and proliferation to IL-7 therapy.
authors.affiliation: Maisonneuve-Rosemont Hospital Research Center, Montreal, QC, Canada.
authors.forename: Olga
authors.initials: O
authors.lastname: Hennion-Tscheltzoff
authors.forename: Dominique
authors.initials: D
authors.lastname: Leboeuf
authors.forename: Simon-David
authors.initials: SD
authors.lastname: Gauthier
authors.forename: Martine
authors.initials: M
authors.lastname: Dupuis
authors.forename: Brigitte
authors.initials: B
authors.lastname: Assouline
authors.forename: Anne
authors.initials: A
authors.lastname: Grégoire
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Thiant
authors.forename: Martin
authors.initials: M
authors.lastname: Guimond
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000502:physiology; D006706:Homeostasis; D015851:Interleukin-7 / Q000008:administration & dosage* / Q000494:pharmacology; D008213:Lymphocyte Activation; D008231:Lymphopenia / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
chemical_list: D018398:Homeodomain Proteins; D015851:Interleukin-7; D035683:MicroRNAs; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D050799:STAT5 Transcription Factor; C529100:mirn181 microRNA, mouse; C064658:RAG-1 protein