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

Severe combined immunodeficiency (SCID) is caused by multiple genetic defects(1-3). The most common form of SCID, X-linked SCID (XSCID), results from mutations in IL2RG (ref. 4), which encodes the common cytokine receptor gamma chain (gamma(c)) that is shared by the IL-2, IL-4, IL-7, IL-9 and IL-15 receptors(1,5-10). In XSCID and SCID resulting from mutations in JAK3, which encodes a Janus family tyrosine kinase that couples to gamma(c) (refs 9,11,12) and is required for gamma(c)-dependent signalling, T- and natural killer (NK)-cells are decreased but B-cell numbers are normal(1-3,13,14) (T-B+NK- SCID). Some SCID patients lack T cells but retain NK cells. Given diminished T-cell development in IL7- or IL7r-deficient mice(15,16) and that Il7r-deficient mice have NK cells(17), 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 suggested(1,18). We now demonstrate medium control 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-7 alpha signalling.