Human lymphoid development in the absence of common γ-chain receptor signaling.
Despite the power of model systems to reveal basic immunologic mechanisms, critical differences exist between species that necessitate the direct study of human cells. Illustrating this point is the difference in phenotype between patients with SCID caused by mutations affecting the common γ-chain (γc) cytokine signaling pathway and mice with similar mutations. Although in both species, null mutations in either IL-2RG (which encodes γc), or its direct downstream signaling partner JAK3, result in T and NK cell deficiency, an associated B cell deficiency is seen in mice but not in humans with these genetic defects. In this study, we applied recent data that have revised our understanding of the earliest stages of lymphoid commitment in human bone marrow (BM) to determine the requirement for signaling through IL-2RG and JAK3 in normal development of human lymphoid progenitors. BM samples from SCID patients with IL-2RG (n = 3) or JAK3 deficiency (n = 2), which produce similar "T-NK-B+" clinical phenotypes, were compared with normal BM and umbilical cord blood as well as BM from children on enzyme treatment for adenosine deaminase-deficient SCID (n = 2). In both IL-2RG- and JAK3-SCID patients, the early stages of lymphoid commitment from hematopoietic stem cells were present with development of lymphoid-primed multipotent progenitors, common lymphoid progenitors and B cell progenitors, normal expression patterns of IL-7RA and TLSPR, and the DNA recombination genes DNTT and RAG1. Thus, in humans, signaling through the γc pathway is not required for prethymic lymphoid commitment or for DNA rearrangement.
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095;
Lisa A
LA
Kohn
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095; Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095;
Christopher S
CS
Seet
Broad Stem Cell Research Center Flow Cytometry Core, University of California, Los Angeles, Los Angeles, CA 90095;
Jessica
J
Scholes
Broad Stem Cell Research Center Flow Cytometry Core, University of California, Los Angeles, Los Angeles, CA 90095;
Felicia
F
Codrea
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095;
Rebecca
R
Chan
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095;
Sania
S
Zaidi-Merchant
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095;
Yuhua
Y
Zhu
Department of Pediatrics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles CA 90095;
Satiro
S
De Oliveira
Division of Research Immunology and Bone Marrow Transplant, Children's Hospital Los Angeles, Los Angeles CA 90027; and.
Neena
N
Kapoor
Department of Pediatrics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles CA 90095; Division of Research Immunology and Bone Marrow Transplant, Children's Hospital Los Angeles, Los Angeles CA 90027; and.
Ami
A
Shah
Division of Research Immunology and Bone Marrow Transplant, Children's Hospital Los Angeles, Los Angeles CA 90027; and.
Hisham
H
Abdel-Azim
Department of Pediatrics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles CA 90095; Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095.
Donald B
DB
Kohn
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095; Department of Pediatrics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles CA 90095; GCrooks@mednet.ucla.edu.
Gay M
GM
Crooks
D000328:Adult; D000818:Animals; D005260:Female; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics / Q000276:immunology*; D053616:Janus Kinase 3 / Q000235:genetics / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
C507941:IL2RG protein, human; D053631:Interleukin Receptor Common gamma Subunit; C507933:JAK3 protein, human; D053616:Janus Kinase 3