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Cited by 177Immunodeficiency and Autoimmune DisordersT-cell and B-cell ImmunologyBlood disorders and treatments

A partial deficiency of interleukin-7Rα is sufficient to abrogate T-cell development and cause severe combined immunodeficiency

Roifman, Chaim M., Zhang, Junyan, Chitayat, David, Sharfe, Nigel·2000·Blood
DOI 10.1182/blood.v96.8.2803
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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)

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Authors
Roifman, C. M., Zhang, J., Chitayat, D., & Sharfe, N.
Affiliations
University of Toronto (CA)
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2000-10-15
Volume
96
Issue
8
Pages
2803-2807
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood.v96.8.2803
OpenAlex
W1510734879
Cited by
177
References
23
Citations by year
2026: 1 · 2025: 5 · 2024: 6 · 2023: 3 · 2022: 5 · 2021: 3 · 2020: 5 · 2019: 8 · 2018: 3 · 2017: 8 · 2016: 8 · 2015: 5 · 2014: 10 · 2013: 9 · 2012: 10
FWCI
2.15
Type
journal article
Language
en
Open access
closed
Locations
  • Blood (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
Keywords
CD127, severe combined immunodeficiency, T cell development, IL-7 signaling, T cell differentiation, B cell development, natural killer cells, proline to serine substitution, consanguinity, antibody deficiency
MeSH terms
Agammaglobulinemia, Animals, Antibody Formation, B-Lymphocytes, Cell Differentiation, Cell Line, Transformed, Consanguinity, Enzyme Activation, Herpesvirus 4, Human, Genes, Recessive, Humans, Immunity, Cellular, Infant, Lymphopenia, Male, Pedigree, Phenotype, Phosphorylation, Protein Binding, Protein Processing, Post-Translational, Protein-Tyrosine Kinases, RNA, Messenger, T-Lymphocytes, Transfection, Signal Transduction, Interleukin-7, Bone Marrow Transplantation, Severe Combined Immunodeficiency, Lymphocyte Count, Cell Lineage, COS Cells, Amino Acid Substitution, Mutation, Missense, Receptors, Interleukin-7, Mice, Janus Kinase 3, Interleukin Receptor Common gamma Subunit

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