INTERLEUKIN-7 RECEPTOR α CHAIN–DEPENDENT SIGNALING IS REQUIRED FOR T-CELL DEVELOPMENT: Basis for T−B+NK+Severe Combined Immunodeficiencies in Humans
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X-LINKED SCID
As mentioned previously, the most common form of SCID is XSCID.6, 45 Affected males have greatly diminished T cells (with thymic hypoplasia and peripheral T lymphopenia) and NK cells, whereas B cells are present in normal or increased numbers. The B cells are nonfunctional, with a defect in immunoglobulin class switching caused, in part, by a lack of T-cell help; however, there is also an intrinsic B-cell defect, as demonstrated by the lack of reconstitution of host B-cell function after
AUTOSOMAL RECESSIVE SCID WITH AN XSCID PHENOTYPE
IL-2 rapidly induces the tyrosine phosphorylation of the Janus tyrosine kinases, Jak1 and Jak3.35, 95 Jak1 associates with IL-2Rβ and Jak3 primarily associates with γc,5, 54, 75 although Jak3, to a lesser degree also can interact with IL-2Rβ.97 The activation of Jak kinases mediates the phosphorylation and activation of signal transducers and activators of transcription (STAT proteins). STAT proteins are latent transcription factors that initially are cytosolic proteins, but once
DEFECTIVE T-CELL AND B-CELL DEVELOPMENT IN Il7−/− AND Il7r−/− MICE
IL-7 is a single-chain 25 kDa glycoprotein26 produced by immune and nonimmune cells, including stromal cells in bone marrow or thymus,59 B-cell lines,4 monocytes and macrophages,82 follicular dendritic cells,40 keratinocytes,29 and intestinal epithelial cells.93 IL-7 is a type I cytokine that is predicted to form a typical four α-helical bundle structure.44 IL-7 was first identified based on its ability to induce in vitro proliferation of murine B-cell progenitors in the absence of stromal
DEFECTIVE IL-7 SIGNALING SEEMS TO ACCOUNT FOR DEFECTIVE T-CELL DEVELOPMENT IN XSCID OR SCID ASSOCIATED WITH JAK3 MUTATIONS, AS PATIENTS WITH MUTATIONS IN THE IL7R GENE HAVE A PROFOUND T-CELL DEFECT
To evaluate whether the defect in IL-7 signaling observed in XSCID or Jak3 deficiency is responsible for the T-cell defect in these diseases, patients with mutations in the genes encoding IL-7 or IL-7Rα were sought. It was hypothesized that such patients would have an autosomal recessive form of SCID of unidentified genetic origin, having no or few T cells but normal or increased B and NK cells.70 Of 108 infants with SCID re-evaluated at Duke University,6 most presented with severe lymphopenia,
WHY DOES DEFECTIVE IL-7 SIGNALING RESULT IN DEFECTIVE T-CELL DEVELOPMENT?
Data have been reviewed that mutations in γc, IL-7Rα, and Jak3 all result in the lack of T-cell development in humans. An important issue is to understand which IL-7 signaling pathway(s) account for the defective T-cell development in these forms of SCID.
After binding to its receptor (IL-7Rα/γc), IL-7 induces the activation of several different signaling pathways (see Fig. 1), including the Jak/STAT pathway,21, 75, 96 the Src family kinases p56lck and p59fyn,64, 91 and phosphatidylinositol
SUMMARY
Two patients with T−B+NK+ SCID were shown to have mutations in their IL7R genes. This discovery indicates that the defect in IL-7 signaling in XSCID and Jak3-deficient patients is probably responsible for their T-cell defect. Both patients had normal or increased numbers of functional NK cells, confirming that IL-7 is not essential for NK-cell development or function. Both patients had normal numbers of B cells, demonstrating that in humans, IL-7 signaling is not essential for B-cell
ACKNOWLEDGMENTS
The authors thank Drs Jian-Xin Lin and Panu Kovanen for critical comments.
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Address reprint requests to Warren J. Leonard, MD, Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 7N252, 9000 Rockville Pike, Bethesda, MD 20892–1674, e-mail: [email protected]
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Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland