Soluble IL-7Rα (sCD127) Inhibits IL-7 Activity and Is Increased in HIV Infection

Crawley, Angela M.; Faucher, Sylvie; Angel, Jonathan B.

doi:10.4049/jimmunol.0903758

Cited by 77 publications

(88 citation statements)

References 54 publications

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“…13 Recently, it was shown that the receptor affinity of the soluble form is comparable to that of the membrane-bound IL-7Ra 14 and that the soluble receptor can inhibit IL-7 signaling in CD8 T cells of HIV patients. 15 Therefore, we investigated whether our results are influenced by complexes between IL-7 and sIL-7Ra. First, we assessed whether the sIL-7Ra enzyme-linked immunosorbent assay (ELISA) is inhibited by IL-7 binding.…”

Section: Resultsmentioning

confidence: 98%

Decreased systemic IL-7 and soluble IL-7Rα in multiple sclerosis patients

et al. 2012

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Polymorphisms (single-nucleotide polymorphism (SNP)) in the interleukin-7 receptor-a (IL-7Ra)/IL-7 pathway are associated with an increased risk to develop multiple sclerosis (MS). The rs6897932 SNP in the IL-7Ra leads to increased soluble IL-7Ra production. Given the functional interaction between sIL-7Ra, membrane-bound IL-7Ra and IL-7, we assessed IL-7, mIL-7Ra and sIL-7Ra levels in MS patients and healthy controls (HCs). One-hundred and twenty eight MS patients had significantly lower sIL-7Ra levels compared with 73 HCs. The levels of sIL-7Ra increased dose-dependent upon rs6897932 [C] risk allele carriership in both HCs and MS. Next, we hypothesized that lower sIL-7Ra could result in a higher mIL-7Ra to soluble IL-7Ra ratio. Indeed, 52 MS patients had significantly increased mIL-7Ra to sIL-7Ra ratio for both CD4 and CD8 T cells compared with 44 HCs. Given the supposed role of IL-7 in autoimmunity, we determined whether sIL-7Ra influences IL-7 levels. IL-7 levels were significantly decreased in 40 MS patients compared with 40 HCs. In conclusion, MS patients had lower free IL-7 and a higher membrane to soluble IL-7Ra ratio. The soluble IL-7Ra levels correlate with the rs6897932 [C] risk allele carriership. The skew at the IL-7 and IL-7Ra level may influence responsiveness of IL-7Ra þ cells.

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Section: Resultsmentioning

confidence: 98%

Decreased systemic IL-7 and soluble IL-7Rα in multiple sclerosis patients

et al. 2012

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“…Another interpretation of the different findings in Caucasians and Africans could be that our initial findings in the Caucasian cohort may not have been related to levels of sIL-7Ra but could have been due to other SNPs in LD with rs6897932, which may have had an influence on CD4 T-cell recovery. This is of course possible but we believe this is less likely given the clear relationship in vitro between sIL-7Ra levels and IL-7 function in primary T-cells, 36,37 and that sIL-7Ra has a binding affinity similar to membrane-bound IL-7Ra on T-cells. 38 Finding the opposite association between genotype and phenotype in replicate genetic studies has been described previously as a 'flip-flop phenomenon,' 39 and is commonly reported in genetic association studies across different ethnic groups.…”

Section: Discussionmentioning

confidence: 98%

The role of SNPs in the α-chain of the IL-7R gene in CD4+ T-cell recovery in HIV-infected African patients receiving suppressive cART

et al. 2011

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We previously found an association between faster CD4 þ T-cell recovery in HIV-infected patients receiving combination antiretroviral therapy (cART) and interleukin-7 receptor-a (IL-7Ra) haplotype-2 in a predominantly Caucasian cohort. This study aims to determine whether this association was also significant in Africans. Patients were recruited from the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort (n ¼ 352). We used survival analysis and linear mixed modelling (LMM) to determine factors associated with CD4 T-cell recovery. Eight IL-7Ra single-nucleotide polymorphisms (SNPs) were genotyped in both Africans and Caucasians (n ¼ 57). Soluble (s)IL-7Ra levels were measured by ELISA. In UARTO, IL-7Ra haplotype-2 was associated with slower CD4 T-cell recovery following cART by using survival analysis (P ¼ 0.020) and no association was found with LMM (P ¼ 0.958). The tagging-SNP for IL-7Ra haplotype-2 (rs6897932) was associated with decreased sIL-7Ra (Po0.001). The haplotypes for the IL-7Ra were significantly different in Africans and Caucasians. Using IL-7Ra genotypes we found slower CD4 T-cell recovery in UARTO patients was still associated with rs6897932 (P ¼ 0.009) and rs3194051 was associated with faster CD4 T-cell recovery (P ¼ 0.006). Unlike Caucasians, we did not demonstrate a significant association between IL-7Ra haplotype 2 and faster CD4 T-cell recovery in Africans. The IL-7Ra SNPs associated with CD4 T-cell recovery following cART differ in African and Caucasian cohorts.

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“…Increased sIL-7R in serum from individuals with human immunodeficiency virus infection may therefore neutralize IL-7-mediated effects on T cells. 21,22 The immune system creates diversity and responds to infection by various adaptive mechanisms, one of them being alternative splicing of cytokine gene products. 23 For instance, alternatively spliced IL-4, lacking exon 2, is produced in response to Mtb infection.…”

Section: Introductionmentioning

confidence: 99%

Increased (6 exon) interleukin-7 production after M. tuberculosis infection and soluble interleukin-7 receptor expression in lung tissue

et al. 2011

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Interleukin-7 (IL-7) and the IL-7 receptor (IL-7R) have been shown to be alternatively spliced in infectious diseases. We tested IL-7 and IL-7R splicing in a tuberculosis (TB)-vaccine/Mycobacterium tuberculosis (Mtb)-challenge model in non-human primates (NHPs). Differential IL-7 splicing was detected in peripheral blood mononuclear cells (PBMCs) from 15/15 NHPs showing 6 different IL-7 spliced isoforms. This pattern did not change after infection with virulent Mtb. We demonstrated increased IL-7 (6 exon) and IL-17 protein production in lung tissue along with concomitant decreased transforming growth factor-b (TGF-b) from NHPs (vaccinated with a recombinant BCG (rBCG)) who showed increased survival after Mtb challenge. IL-7 increased IL-17 and interferon-g (IFN-g) gene and protein expression in PBMCs. Mtb-infected NHPs showed differential IL-7R splicing associated with the anatomical location and tissue origin, that is, in lung tissue, hilus, axillary lymph nodes (LNs) and spleen. Differential splicing of the IL-7R was typical for healthy (non-Mtb infected) and for Mtb-infected lung tissue with a dominant expression of soluble IL-7R (sIL-7R) receptor lacking exon 6 (9:1 ratio of sIL-7R/cell-bound IL-7R). Differential ratios of cell-bound vs sIL-7R could be observed in hilus and axillary LNs from Mtb-infected NHPs with an inversed ratio of 1:9 (sIL-7R/cell-bound IL-7R) in spleen and PBMCs. Soluble IL-7R is exclusively present in lung tissue.

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Soluble IL-7Rα (sCD127) Inhibits IL-7 Activity and Is Increased in HIV Infection

Cited by 77 publications

References 54 publications

Decreased systemic IL-7 and soluble IL-7Rα in multiple sclerosis patients

Decreased systemic IL-7 and soluble IL-7Rα in multiple sclerosis patients

The role of SNPs in the α-chain of the IL-7R gene in CD4+ T-cell recovery in HIV-infected African patients receiving suppressive cART

Increased (6 exon) interleukin-7 production after M. tuberculosis infection and soluble interleukin-7 receptor expression in lung tissue

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