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Defective IL7R expression in T-B+NK+ severe combined immunodeficiency

Abstract

Severe combined immunodeficiency (SCID) is caused by multiple genetic defects1,2,3. The most common form of SCID, X-linked SCID (XSCID), results from mutations in IL2RG (ref. 4), which encodes the common cytokine receptor γ chain (γc) that is shared by the IL-2, IL-4, IL-7, IL-9 and IL-15 receptors1,5,6,7,8,9,10. In XSCID and SCID resulting from mutations in JAK3, which encodes a Janus family tyrosine kinase that couples to γc (Refs 9,12) and is required for γc-dependent signalling, T- and natural killer (NK)-cells are decreased but B-cell numbers are normal1,2,3,13,14 (T-B+NK- SCID). Some SCID patients lack T cells but retain NK cells. Given diminished T-cell development in Il7- or Il7r-deficient mice15,16 and that Il7r-deficient mice have NK cells17, we hypothesized that TB+NK+ SCID might result from defective IL-7 signalling, although apparent differences in the role of the IL-7/IL-7R pathway in humans and mice in T-cell and B-cell development have been suggested1,18. We now demonstrate that defective IL7R expression causes TB+NK+ SCID, indicating that the T-cell, but not the NK-cell, defect in XSCID results from inactivation of IL-7Rα signalling.

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Figure 1: Normal IL7 and defective IL7R mRNA levels in two TB+NK+SCID patients.
Figure 2: IL7R sequencing for patients 1 and 2 and their parents.
Figure 3: Signalling by wild-type and patient 1 IL-7Rα constructs.

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Acknowledgements

We thank T. Hollingsorth and D. Cosman for providing the DNA sequence of human IL7R, M. Noguchi for help with iodinating IL-7 and advice on 125I-IL-7 binding assays, S. John for advice on the in vitro reconstitution experiments of IL-7-induced Stat5 DNA-binding activity and transcriptional activation, M. Polymeropoulos and M. Erdos for providing CEPH DNA and T. Waldmann, A. Sher, K. Kidd, J. Belmont and D. Ascherman for critical comments and valuable discussions. A.P. was supported in part by a grant from the Association pour la Recherche du Cancer.

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Correspondence to Warren J. Leonard..

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Puel, A., Ziegler, S., Buckley, R. et al. Defective IL7R expression in T-B+NK+ severe combined immunodeficiency. Nat Genet 20, 394–397 (1998). https://doi.org/10.1038/3877

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