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Blood, 15 October 2000, Vol. 96, No. 8, pp. 2803-2807
IMMUNOBIOLOGY
A partial deficiency of interleukin-7R is sufficient to
abrogate T-cell development and cause severe combined
immunodeficiency
Chaim M. Roifman,
Junyan Zhang,
David Chitayat, and
Nigel Sharfe
From the Divisions of Immunology/Allergy and Clinical
Genetics, Department of Paediatrics, The Infection, Immunity, Injury
and Repair Program, Research Institute, The Hospital for Sick Children
and The University of Toronto, Canada.
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-7R and the  common (c) chain, this
lymphocyte receptor system is critical for T lineage but not for B
lineage development. Indeed, complete c deficiency like IL-7R
deficiency results in the arrest of T-cell but not B-cell development
(T B+ SCID). However, partial deficiency of
c 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-7R, like partial c deficiency may lead to a
milder clinical and immunologic phenotype. A P132S mutation in the
IL-7R 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-7R did not affect IL-7R 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-7R. Surprisingly, this
partial deficiency of IL-7R resulted in a severe phenotype,
including markedly reduced circulating T cells while sparing B-cell
numbers similar to c chain deficiency. However, unlike the
previously reported cases, serum immunoglobulins were virtually absent.
Further, unlike c deficiency, NK cell numbers and function was
preserved. Despite the partial deficiency, clinical presentation was
indistinguishable from a complete c deficiency, including severe and
persistent viral and protozoal infections and failure to thrive. Unlike
partial c deficiency, a partial deficiency of IL-7R results in an
arrest of T-cell development, leading to typical severe combined
immunodeficiency. This underscores the critical role of IL-7R chain
in the differentiation of T cells.
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