INTERLEUKIN-7 RECEPTOR α CHAIN–DEPENDENT SIGNALING IS REQUIRED FOR T-CELL DEVELOPMENT: Basis for TB+NK+Severe Combined Immunodeficiencies in Humans

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Severe combined immunodeficiencies (SCIDs) are inherited diseases that represent the most severe forms of primary immunodeficiencies, affecting approximately 1 child out of every 80,000 live births. These diseases are characterized by profound defects in cellular and humoral immunity. As a result, affected individuals typically die within the first year of life because of recurrent opportunistic infections, unless they receive successful bone marrow transplants. SCID is most appropriately described as a syndrome with diverse genetic origins. Because of advances made in genetics and molecular biology, it has become possible to identify the genes responsible for many forms of SCID, although approximately 30% of cases have unknown causes.6, 20, 45

In this article, SCID refers to cases of inherited immunodeficiency characterized by a marked decrease in T cells, as previously defined.20 Patients with other inherited immunodeficiencies, such as those resulting from mutations in the T-cell receptor (TCR)–associated chains, CD3γ or CD3ε, or in the TCR-associated tyrosine kinase ZAP-70, may have normal or decreased numbers of T cells, but typically do not develop life-threatening infections in the first months of life.20 Patients with SCID then can be classified into four groups according to their basic immunologic phenotypes (Table 1). In all four groups, T cells are almost uniformly decreased in numbers; however, the levels of B and natural killer (NK) cells are more variable. In the first group, T, B, and NK cells are all diminished (TBNK SCID). The most severe form in this group is reticular dysgenesis, a disease in which the lymphoid and myeloid systems are affected.18 The responsible gene for this form of SCID has not been identified. Adenosine deaminase (ADA) deficiency is less severe, but still also is characterized by a profound block in lymphocyte maturation.30 Mutations in the ADA gene result in the accumulation of dATP in cells, therefore inhibiting cell division. The major impact of ADA deficiency is in the immune system. In the second group, T and B cells are diminished but NK cells are not (TBNK+ SCID). Approximately 20% of all patients with SCID have such a block in T- and B-lymphocyte differentiation because of a defect in the recombination process.83 This group can be divided in two subgroups: one with a normal cell radiosensitivity, resulting from mutations in the RAG1 or RAG2 genes, which are responsible for the initiation of the V(D)J rearrangement process,1, 80 and the other with an increased cell radiosensitivity, in which the involved gene(s) have not been identified.11 The third and fourth groups are characterized by the presence of B cells (TB+ SCID); however, the B cells are usually nonfunctional, in part because of an absence of T-cell help.13 The third group is characterized by the absence of NK cells (TB+NK SCID). The most frequent form of SCID in this group—and indeed the most common overall form of SCID is X-linked SCID (XSCID). In XSCID, which accounts for almost 50% of cases of SCID, patients have profoundly diminished numbers of T cells and NK cells, but normal or increased numbers of B cells.45, 47 XSCID was found to result from mutations in the gene encoding the γ chain of the interleukin-2 (IL-2) receptor.61 As discussed below, IL-2Rγ is now denoted as the common cytokine receptor γ chain, γc, because it is shared by the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15.24, 36, 38, 39, 60, 61, 75, 76, 87 The XSCID phenotype also has been found in patients with an autosomal recessive form of SCID, and it was hypothesized that this form of SCID could result from mutations in the gene coding for the tyrosine kinase Jak3,75 which associates with γc and is activated by IL-2, IL-4, IL-7, IL-9, and IL-15.48 Finally, the fourth group of SCID consists of patients with a selective T-cell defect (TB+NK+ SCID). One of the genetic causes for this syndrome is defective expression of IL-7Rα,70 which is the principal focus of this article.

Section snippets

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 TB+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

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