A partial deficiency of interleukin-7Rα 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 natural killer (NK) cells in the mouse. In humans, although both T-cell and B-cell progenitors express the functional IL-7 receptor that consists of IL-7Rα and the γcommon (γc) chain, this lymphocyte receptor system is critical for T lineage but not for B lineage development. Indeed, complete γc deficiency like IL-7Rα deficiency results in the arrest of T-cell but not B-cell development (T−B+ SCID). However, partial deficiency of γc caused by missense mutations results in a T+B+ phenotype and a delay of clinical presentation. It was therefore plausible to assume that partial deficiency of IL-7Rα, like partial γc deficiency may lead to a milder clinical and immunologic phenotype. A P132S mutation in the IL-7Rα was identified in 3 patients with severe combined immunodeficiency (SCID) within an extensively consanguineous family. Substitution of proline with serine in the extracellular portion of IL-7Rα did not affect IL-7Rα messenger RNA (mRNA) and protein expression, but severely compromised affinity to IL-7, resulting in defective signal transduction. In response to IL-7 stimulation, Jak-3 phosphorylation was markedly reduced in both patient cells as well as in COS cells reconstituted with mutant IL-7Rα. Surprisingly, this partial deficiency of IL-7Rα resulted in a severe phenotype, including markedly reduced circulating T cells while sparing B-cell numbers similar to γc chain deficiency. However, unlike the previously reported cases, serum immunoglobulins were virtually absent. Further, unlike γc deficiency, NK cell numbers and function was preserved. Despite the partial deficiency, clinical presentation was indistinguishable from a complete γc deficiency, including severe and persistent viral and protozoal infections and failure to thrive. Unlike partial γc deficiency, a partial deficiency of IL-7Rα results in an arrest of T-cell development, leading to typical severe combined immunodeficiency. This underscores the critical role of IL-7Rα chain in the differentiation of T cells.

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