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

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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 γ c-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 T–B+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 T–B +NK+ SCID, indicating that the T-cell, but not the NK-cell, defect in XSCID results from inactivation of IL-7Rα signalling.