Interleukin-2 Receptor γ Chain: a Functional Component of the Interleukin-7 Receptor

Noguchi, Masayuki; Nakamura, Yoshiaki; Russell, Sarah M.; Ziegler, Steven F.; Tsang, Monica; Cao, Xiqing; Leonard, Warren J.

doi:10.1126/science.8266077

Cited by 910 publications

(376 citation statements)

References 31 publications

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“…[20,21]. The IL-7Ra chain heterodimerizes with the common gamma (c C ) chain [22,23] to form the receptor for IL-7, while together with the thymic stromal lymphopoietin (TSLP) receptor chain [24,25], it forms the receptor for TSLP. Expansion at the pre-BII stage is dependent on the expression of the pre-BCR.…”

Section: Leukocyte Signalingmentioning

confidence: 99%

Both the pre-BCR and the IL-7Rα are essential for expansion at the pre-BII cell stagein vivo

et al. 2005

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During B cell development, proliferative expansion takes place after expression of the pre-BCR. At this pre-BII cell stage, the IL-7Ra is also expressed. Some in vitro studies suggest that pre-BCR-dependent expansion relies on the IL-7Ra, and others that it does not. It has also been suggested that the pre-BCR mediates down-regulation of the IL7Ra. However, the in vivo relationship between the pre-BCR and the IL-7Ra has not been previously examined. Here, we have investigated this by establishing mice lacking both receptors. Our results show that in the absence of the IL-7Ra, the pre-BII population is reduced, as previously seen in mice lacking the pre-BCR, demonstrating that the IL-7Ra is important at this stage. A deficiency in both receptors results in a further reduction of the pre-BII cell population. We conclude that both the IL-7Ra and the pre-BCR are required for optimal pre-BII cell expansion. Furthermore, IL-7Ra expression levels are normal in pre-BCR-deficient mice, suggesting that the pre-BCR does not mediate its down-regulation. As a consequence of the absence of both receptors, the peripheral B cell pool is severely depleted, resulting in atypical splenic B cell structures and reduced serum Ig levels. IntroductionB lymphopoiesis takes place in the fetal liver and, postnatally, in the BM [1][2][3]. During early BM B cell development, critical checkpoints occur firstly after Ig heavy (H)-chain DJ H rearrangement and secondly after successful VDJ H rearrangement. Due to the inherent imprecision of the rearrangement process, each of these is followed by proliferative expansion at the pre-BI (DJ H ) and large pre-BII (VDJ H ) cell stages, which results in an increase in cell numbers and, consequently, the Ig repertoire. Functional VDJ H -rearrangement leads to expression of the lH chain, which, together with the surrogate light chain (SLC, comprised of VpreB and k5) [4, 5], forms the pre-B cell receptor (pre-BCR) [6][7][8]. After subsequent Ig light (L)-chain recombination, although not followed by an expansion phase, the end result is the production of large numbers of immature B cells, each carrying a unique BCR (IgM) on the cell surface. Immature B cells migrate to the spleen, where they mature and co-express IgD [9].Expansion at the pre-BI cell stage has been shown, both in vitro [10][11][12][13] and in vivo [14][15][16][17][18][19][20][21], to depend on the IL-7Ra [22]. Mice deficient in the IL-7Ra chain show a block in B cell development at the pre-BI stage. Although this block is complete in adult IL-7Ra -/-mice, Leukocyte signalingThe last two authors contributed equally to this work. [20,21]. The IL-7Ra chain heterodimerizes with the common gamma (c C ) chain [22,23] to form the receptor for IL-7, while together with the thymic stromal lymphopoietin (TSLP) receptor chain [24,25], it forms the receptor for TSLP. Expansion at the pre-BII stage is dependent on the expression of the pre-BCR. While a lack of the transmembrane region of the lH chain (lMT) leads to a complete block at the pre-BI stag...

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Section: Leukocyte Signalingmentioning

confidence: 99%

Both the pre-BCR and the IL-7Rα are essential for expansion at the pre-BII cell stagein vivo

et al. 2005

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“…This family of cytokines includes IL-2, IL-4, IL-7, IL-9 and IL-15, each of which shares the IL-2 receptor g chain (IL-2Rg) as a receptor component (Giri et al, 1994;Kondo et al, 1993Kondo et al, , 1994Noguchi et al, 1993a;Russell et al, 1993Russell et al, , 1994; Figure 1). Because of its shared nature, IL-2Rg is now known as the common cytokine receptor g chain (g c ) (Leonard, 1996).…”

Section: An Overview Of Il-2 Family Cytokinesmentioning

confidence: 99%

The role of Stat5a and Stat5b in signaling by IL-2 family cytokines

2000

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“…Importantly, IL7Ra is a key functional marker of the early heterogeneity observed in effector T cells. [6][7][8] Both naive and memory T cells express high levels of IL7Ra, and IL7 is required for their homeostasis. 9 Activation of T cells results in the downregulation of IL7Ra within 48 h after antigenic stimulation, but there is re-expression on the resting memory pool during the course of an immune response.…”

Section: Introductionmentioning

confidence: 99%

Variation in IL7R predisposes to sarcoid inflammation

et al. 2009

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Sarcoidosis is a chronic granulomatous disorder characterized by a massive influx of Th1 lymphocytes. Both naive and memory T cells express high levels of interleukin 7 receptor-a (IL7Ra), encoded by the IL7R gene. The purpose of this study was to investigate the role of the IL7R gene region in susceptibility to sarcoidosis. Six common single-nucleotide polymorphisms (SNPs) spanning IL7R were genotyped and analyzed in 475 sarcoidosis patients and 465 healthy controls. Replication of one significant associated SNP was carried out in 206 independent sarcoidosis patients, 127 controls and 126 patients with Lö fgren's disease. The rs10213865 SNP was associated with sarcoidosis (P ¼ 0.008), and in silico analysis showed a complete linkage (r 2 ¼ 1, D 0 ¼ 1) with a functional nonsynonymous coding SNP in exon 6 (rs6897932, T244I). Combined analysis of 663 individuals with sarcoidosis and 586 controls (homozygous carriers of risk allele, P ¼ 5 Â 10 À4 , odds ratio ¼ 1.49 (1.19-1.86)) provided strong statistical support for a genuine association of IL7R with the risk of sarcoidosis. In addition, we report the same trend between variation in the IL7R gene and patients with Lö fgren's disease, suggesting that variation in IL7R may confer general risk for developing granulomatous lung disease.

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Interleukin-2 Receptor γ Chain: a Functional Component of the Interleukin-7 Receptor

Cited by 910 publications

References 31 publications

Both the pre-BCR and the IL-7Rα are essential for expansion at the pre-BII cell stagein vivo

Both the pre-BCR and the IL-7Rα are essential for expansion at the pre-BII cell stagein vivo

The role of Stat5a and Stat5b in signaling by IL-2 family cytokines

Variation in IL7R predisposes to sarcoid inflammation

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