Cell biology of IL-7, a key lymphotrophin

Jiang, Qiong; Li, Wen Qing; Aiello, Francesca; Mazzucchelli, Renata; Asefa, Benyam; Khaled, Annette R.; Durum, Scott K.

doi:10.1016/j.cytogfr.2005.05.004

Cited by 295 publications

(320 citation statements)

References 275 publications

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“…[8,9] These two genes are plausible biological candidates for MS since the proteins they encode, interleukin 2 receptor alpha (IL2Rα, also known as CD25) and interleukin 7 receptor alpha (IL7Rα, also known as CD127), play a fundamental role in lymphocyte development and the modulation of T cell effector function. [18,19] The goal of this study is to further define the role of IL2RA rs2104286 and IL7R rs6897932 in the susceptibility to MS. To this end, we characterized these two variants in a case-control series of MS patients from Canada. This cohort is noticeably distinct from those described in most association studies of IL2RA and IL7R with MS, [8,9] as it contains a higher proportion of patients with a family history of disease (82.5%), as well as a higher number of patients presenting PPMS (25%).…”

Section: Discussionmentioning

confidence: 99%

Genetic variants in IL2RA and IL7R affect multiple sclerosis disease risk and progression

et al. 2014

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Multiple sclerosis (MS) is a common demyelinating neurodegenerative disease with a strong genetic component. Previous studies have associated genetic variants in IL2RA and IL7R in the pathophysiology of the disease. In this study we describe the association between IL2RA (rs2104286) and IL7R (rs6897932) in the Canadian population. Genotyping 1,978 MS patients and 830 controls failed to identify any significant association between these variants and disease risk. However, stratified analysis for family history of disease, and disease course identified a trend towards association for IL2RA in patients without a family history (p = 0.05; odds ratio = 0.77), and a significant association between IL7R and patients who developed progressive MS (PrMS) (p = 0.002; odds ratio = 0.73).Although not statistically significant, the effect of IL2RA (rs2104286) in patients without a family history of MS indicates that the genetic components for familial and sporadic disease are perhaps distinct. This data suggests the onset of sporadic disease is likely determined by a large number of variants of small effect, whereas MS in patients with a family history of disease is caused by a few deleterious variants. In addition, the significant association between PrMS and rs6897932 indicates that IL7R may not be disease-causing but a determinant of disease course. Further characterization of the effect of IL2RA and IL7R genetic variants in defined MS subtypes is warranted to evaluate the effect of these genes on specific clinical outcomes and to further elucidate the mechanisms of disease onset and progression.

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Section: Discussionmentioning

confidence: 99%

Genetic variants in IL2RA and IL7R affect multiple sclerosis disease risk and progression

et al. 2014

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“…IL-7 acts as a survival factor for resting naive and memory T cells through maintaining a balanced activity of several antiapoptotic and proapoptotic members of the Bcl-2 family and through the regulation of metabolic processes (21). However, little is known about the effect of IL-7 on Fas-mediated T cell apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…IL-7 is a stromal cell-derived cytokine acting on peripheral naive and memory cells as an essential survival factor (21)(22)(23)(24)(25). IL-7 also promotes T cell activation (26) and memory formation (27,28).…”

mentioning

confidence: 99%

Potential Role for IL-7 in Fas-Mediated T Cell Apoptosis During HIV Infection

Fluur

Milito

Fry

et al. 2007

The Journal of Immunology

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IL-7 promotes survival of resting T lymphocytes and induces T cell proliferation in lymphopenic conditions. As elevated IL-7 levels occur in HIV-infected individuals in addition to high Fas expression on T cells and increased sensitivity to Fas-induced apoptosis, we analyzed whether IL-7 has a regulatory role in Fas-mediated T cell apoptosis. We show that IL-7 up-regulates Fas expression on naive and memory T cells through a mechanism that involves translocation of Fas molecules from intracellular compartments to the cell membrane. IL-7 induced the association of Fas with the cytoskeletal component ezrin and a polarized Fas expression on the cell surface. The potential role of IL-7 in Fas up-regulation in vivo was verified in IL-7-treated macaques and in HIV-infected or chemotherapy treated patients by the correlation between serum IL-7 levels and Fas expression on T cells. IL-7 treatment primed T cells for Fas-induced apoptosis in vitro and serum IL-7 levels correlated with the sensitivity of T cells to Fas-induced apoptosis in HIV-infected individuals. Our data suggest an important role for IL-7 in Fas-mediated regulation of T cell homeostasis. Elevated IL-7 levels associated with lymphopenic conditions, including HIV-infection, might participate in the increased sensitivity of T cells for activation-induced apoptosis.

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“…[36][37][38] It is secreted by stromal cells in the bone marrow and thymus. 30 Recently, we and others reported that hepatocytes could produce IL-7 that functions both locally and systemically. 17,18,24 In murine autoimmune diabetes models, the blockade of IL-7R upregulated PD-1 expression in autoreactive T cells, and the administration of recombinant IL-7 suppressed PD-1 levels.…”

Section: Discussionmentioning

confidence: 99%

“…However, Annexin V staining revealed that in the absence of accessory signaling, the survival of CD8 1 T cells was significantly decreased compared to fully activated cells (Figure 4c). homeostasis, 30,31 in response to Toll-like receptor 4 (TLR4) and Type I interferon (IFN-I) signaling. 17,18 To further explore its modulatory effects on T-cell function in viral hepatitis, we examined whether IL-7 inhibits PD-1 expression on T cells.…”

Section: Lack Of Ifn-i Signaling Increases Pd-1 Level In Hepatic Ctlsmentioning

confidence: 99%

Type 1 interferon-induced IL-7 maintains CD8+ T-cell responses and homeostasis by suppressing PD-1 expression in viral hepatitis

et al. 2014

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Type 1 interferon (IFN-I) promotes antigen-presenting cell maturation and was recently shown to induce hepatic IL-7 production during infection. Herein, we further explored the underlying mechanisms used by IFN-I to orchestrate antiviral immune responses in the liver. Acute viral hepatitis was induced by i.v. injection of adenovirus (Ad) in IFN-a receptor knockout (IFNAR 2/2 ) and control mice. To disrupt signaling, monoclonal antibodies (mAbs) against IL-7 receptor alpha (IL-7Ra) or PD-L1 were i.p. injected. We found that CD8 1 T cells in IFNAR 2/2 mice were less effective than those in control mice. The reduced T-cell function was accompanied by increased levels of PD-1 expression, apoptosis and decreased IFN-c production. The lack of IFN-I signaling also impaired the expression of accessory molecules in both intrahepatic dendritic cell (DCs) and hepatocytes. PD-L1 was comparably and highly expressed on hepatocytes in both IFNAR 2/2 and control mice. Injection of PD-L1-specific mAb in IFNAR 2/2 mice reversed the compromised immune responses in the liver. Further investigation showed that hepatic IL-7 elevation was less pronounced in IFNAR 2/2 mice compared to the controls. A treatment with recombinant IL-7 suppressed PD-1 expression on CD8 1 T cells in vitro. Accordingly, blocking IL-7R signaling in vivo resulted in increased PD-1 expression on CD8 1 T cells in Ad-infected mice. Collectively, the results suggest that IFN-I-induced hepatic IL-7 production maintains antiviral CD8 1 T-cell responses and homeostasis by suppressing PD-1 expression in acute viral hepatitis.

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Cell biology of IL-7, a key lymphotrophin

Cited by 295 publications

References 275 publications

Genetic variants in IL2RA and IL7R affect multiple sclerosis disease risk and progression

Genetic variants in IL2RA and IL7R affect multiple sclerosis disease risk and progression

Potential Role for IL-7 in Fas-Mediated T Cell Apoptosis During HIV Infection

Type 1 interferon-induced IL-7 maintains CD8+ T-cell responses and homeostasis by suppressing PD-1 expression in viral hepatitis

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