title: A partial deficiency of interleukin-7R alpha is sufficient to abrogate T-cell development and cause severe combined immunodeficiency.
abstract: Both in vitro and in vivo studies established that interleukin 7 (IL-7) is essential for differentiation of immature T cells and B cells but not natural killer (NK) cells in the mouse. In humans, although both T-cell and B-cell progenitors express the functional IL-7 receptor that consists of IL-7R alpha and the gamma common (gamma c) chain, this lymphocyte receptor system is critical for T lineage but not for B lineage development. Indeed, complete gamma c deficiency like IL-7R alpha deficiency results in the arrest of T-cell but not B-cell development (T(-)B(+) SCID). However, partial deficiency of gamma c caused by missense mutations results in a T(+)B(+) phenotype and a delay of clinical presentation. It was therefore plausible to assume that partial deficiency of IL-7R alpha, like partial gamma c deficiency may lead to a milder clinical and immunologic phenotype. A P132S mutation in the IL-7R alpha was identified in 3 patients with severe combined immunodeficiency (SCID) within an extensively consanguineous family. Substitution of proline with serine in the extracellular portion of IL-7R alpha did not affect IL-7R alpha messenger RNA (mRNA) and protein expression, but severely compromised affinity to IL-7, resulting in defective signal transduction. In response to IL-7 stimulation, Jak-3 phosphorylation was markedly reduced in both patient cells as well as in COS cells reconstituted with mutant IL-7R alpha. Surprisingly, this partial deficiency of IL-7R alpha resulted in a severe phenotype, including markedly reduced circulating T cells while sparing B-cell numbers similar to gamma c chain deficiency. However, unlike the previously reported cases, serum immunoglobulins were virtually absent. Further, unlike gamma c deficiency, NK cell numbers and function was preserved. Despite the partial deficiency, clinical presentation was indistinguishable from a complete gamma c deficiency, including severe and persistent viral and protozoal infections and failure to thrive. Unlike partial gamma c deficiency, a partial deficiency of IL-7R alpha results in an arrest of T-cell development, leading to typical severe combined immunodeficiency. This underscores the critical role of IL-7R alpha chain in the differentiation of T cells. (Blood. 2000;96:2803-2807)
authors.affiliation: Division of Immunology/Allergy, Department of Paediatrics, The Hospital for Sick Children, Toronto, Canada. croifman@sickkids.on.ca
authors.forename: C M
authors.initials: CM
authors.lastname: Roifman
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: D
authors.initials: D
authors.lastname: Chitayat
authors.forename: N
authors.initials: N
authors.lastname: Sharfe
mesh_terms: D000361:Agammaglobulinemia / Q000235:genetics; D019943:Amino Acid Substitution; D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000378:metabolism; D016026:Bone Marrow Transplantation; D019556:COS Cells; D002454:Cell Differentiation; D002461:Cell Line, Transformed; D019070:Cell Lineage; D003241:Consanguinity; D004789:Enzyme Activation; D005808:Genes, Recessive; D004854:Herpesvirus 4, Human; D006801:Humans; D007111:Immunity, Cellular; D007223:Infant; D053631:Interleukin Receptor Common gamma Subunit; D015851:Interleukin-7 / Q000502:physiology*; D053616:Janus Kinase 3; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000235:genetics; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D010766:Phosphorylation; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020395:Receptors, Interleukin-7 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000473:pathology*; D014162:Transfection
chemical_list: C507941:IL2RG protein, human; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D015851:Interleukin-7; D012333:RNA, Messenger; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3