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

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 natur al killer (NK) cells in the mouse. In humans, although both T-cell and B-ce ll 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, compl ete 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 p artial 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 prolin e with serine in the extracellular portion of IL-7R alpha did not affect IL -7R alpha messenger RNA (mRNA) and protein expression, but severely comprom ised affinity to IL-7, resulting in defective signal transduction. In respo nse 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 alph a. Surprisingly, this partial deficiency of IL-7R alpha resulted in a sever e phenotype, including markedly reduced circulating T cells while sparing B -cell numbers similar to gamma c chain deficiency. However, unlike the prev iously reported cases, serum immunoglobulins were virtually absent. Further , unlike gamma c deficiency, NK cell numbers and function was preserved. De spite the partial deficiency, clinical presentation was indistinguishable f rom a complete gamma c deficiency, including severe and persistent viral an d protozoal infections and failure to thrive. Unlike partial gamma c defici ency, a partial deficiency of IL-7R alpha results in an arrest of T-cell de velopment, leading to typical severe combined immunodeficiency. This unders cores the critical role of IL-7R alpha chain in the differentiation of T ce lls. (Blood. 2000;96:2803-2807) (C) 2000 by The American Society of Hematol ogy.