Interleukin-7 is a critical growth factor in early human T-cell development.
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, and may explain the absence or highly reduced levels of T cells in patients with X-linked SCID. The molecular defect in these patients has been shown to be a mutation in the gamma chain of the IL-2R. Although this gamma chain is not only present in the IL-2R, but also forms an essential part of other cytokine receptors, including IL-4, IL-7, IL-9, IL-13, and IL-15, the T-cell defect in these patients can be explained by the fact that IL-7 is not able to transduce its signal by the molecular defect of the common gamma (gamma c) chain and that IL-7 is indispensable for T-cell development.
Plum
J
J
Department of Clinical Chemistry, Microbiology, and Immunology, University Hospital of Ghent, Belgium.
De Smedt
M
M
Leclercq
G
G
Verhasselt
B
B
Vandekerckhove
B
B
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D018952:Antigens, CD34 / Q000032:analysis; D002454:Cell Differentiation; D019070:Cell Lineage; D002678:Chimera; D005260:Female; D016332:Fetal Tissue Transplantation; D006411:Hematopoiesis, Extramedullary / Q000502:physiology*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015851:Interleukin-7 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D008099:Liver / Q000166:cytology* / Q000196:embryology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011247:Pregnancy; D018121:Receptors, Cytokine / Q000172:deficiency / Q000235:genetics; D018123:Receptors, Interleukin / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000172:deficiency / Q000235:genetics; D020395:Receptors, Interleukin-7; D013047:Specific Pathogen-Free Organisms; D013601:T-Lymphocytes / Q000166:cytology*; D013950:Thymus Gland / Q000166:cytology / Q000196:embryology*; D014183:Transplantation, Heterologous; D016042:Transplantation, Heterotopic
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018952:Antigens, CD34; D015851:Interleukin-7; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D015375:Receptors, Interleukin-2; D020395:Receptors, Interleukin-7