Interleukin-15 and the regulation of lymphoid homeostasis

Lodolce, James P.; Burkett, Patrick R.; Koka, Rima; Boone, David L.; Chien, Marcia; Chan, Faye; Madonia, Michelle; Chai, Sophia; Ma, Averil

doi:10.1016/s0161-5890(02)00211-0

Cited by 64 publications

(49 citation statements)

References 69 publications

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“…The IL-2 signaling pathway essentially entirely overlaps with that induced by IL-15, as both the IL-2 and IL-15 receptors share identical ␤ and common ␥-chain subunits (42), yet continued culture with IL-2 favors effector rather than memory T cells. This dichotomy between IL-2 and IL-15 signaling has been noted previously (43,44). One explanation for the distinct outcomes of IL-2 vs IL-15 or IL-7 for CD8 ϩ T cells may simply be related to the strength of signal, as other studies have shown that the culture of Ag-activated CD8 ϩ T cells with a suboptimal dose of IL-2 in vitro primarily yielded memory phenotypic T cells (27).…”

Section: Discussionmentioning

confidence: 67%

Initial Antigen Encounter Programs CD8+ T Cells Competent to Develop into Memory Cells That Are Activated in an Antigen-Free, IL-7- and IL-15-Rich Environment

Carrió

Bathe

Malek

2004

The Journal of Immunology

111

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Although much is known concerning the immunobiology of CD8+ T memory cells, the initial events favoring the generation of CD8+ T memory cells remain poorly defined. Using a culture system that yields memory-like CD8+ T cells, we show that 1 day after Ag encounter, Ag-activated T cells developed into memory-like T cells, but this optimally occurred 3 days after Ag encounter. Key phenotypic, functional, and molecular properties that typify central memory T cells were expressed within 48 h when the activated CD8+ T cells were cultured with IL-7 or IL-15 in the absence of Ag or following transfer into normal mice. These data support a model whereby Ag activation of naive CD8+ T cells not only programs effector cell expansion and contraction but the potential to develop into a memory cell which ensues in an Ag-free environment containing IL-7 or IL-15.

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Section: Discussionmentioning

confidence: 67%

Initial Antigen Encounter Programs CD8+ T Cells Competent to Develop into Memory Cells That Are Activated in an Antigen-Free, IL-7- and IL-15-Rich Environment

Carrió

Bathe

Malek

2004

The Journal of Immunology

111

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“…It has been demonstrated that the lack of either IL-15 or IL15Ra causes a decrease in the frequency of memory CD8 1 T cells, 1,23 and that IL-15 is required mainly for the maintenance of antigen-experienced memory CD8 1 T cells and not for their generation. 12,24 We have shown previously that CD8 1 T cells from diabetic 8.3-NOD mice expressing a highly pathogenic transgenic TCR on CD8 1 T cells caused T1D following adoptive transfer 16 surprisingly NOD.scid.Il15ra -/-recipients developed T1D with frequency and kinetics similar to that of control NOD.scid recipients (Figure 1c and e, middle panel).…”

Section: Resultsmentioning

confidence: 99%

“…1,2 Even though IL-15 mRNA can be detected in different organs such as placenta, skeletal muscle, intestine and kidney under steady state, 3 the protein expression is below the level of detection by conventional methods and is limited to macrophages and dendritic cells (DCs). 4 IL-15 protein can be expressed with either a short or a long signal peptide (SSP and LSP, respectively).…”

Section: Introductionmentioning

confidence: 99%

Trans-presentation of interleukin-15 by interleukin-15 receptor alpha is dispensable for the pathogenesis of autoimmune type 1 diabetes

et al. 2016

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Interleukin-15 (IL-15) is a pro-inflammatory cytokine that is required for the survival and activation of memory CD8 1 T cells, natural killer (NK) cells, innate lymphoid cells, macrophages and dendritic cells. IL-15 is implicated in the pathogenesis of various autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, psoriasis and autoimmune type 1 diabetes (T1D). IL-15 receptor (IL-15R) consists of a specific a chain, the b chain that is shared with IL-2R and the common c chain. IL-15 is unique in the manner in which it binds and signals through its receptor subunits. IL-15 that is complexed with IL-15Ra binds to the bc receptor complex present on the responding cell to mediate its biological effects through a process referred to as trans-presentation. The trans-presented IL-15 is essential to mediate the biological effects on T lymphocytes and NK cells. Here we show that IL-15, but not IL-15Ra, is required for the development of spontaneous and virus-induced T1D, viral clearance and for antigen cross-presentation to CD8 1 T lymphocytes. Our findings provide insight into the complexities of IL-15 signalling in the initiation and maintenance of CD8 1 T cell-mediated immune responses. Cellular & Molecular Immunology

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“…As indicated by in vivo studies, patients who demonstrate Th2 dominance tend to develop chronic infection, whereas those with a Th1 phenotype can clear Of the ISGs analyzed, IL-15, a unique target of IRF-1, was also substantially reduced in both hepatic and T cells expressing either the entire HCV replicon or the structural proteins, and to our knowledge this is the first study reporting a repression of IL-15 in cells bearing the entire HCV replicon. IL-15 is involved in the activation and homeostatic maintenance of cells of both the innate and adaptive immune systems, playing a key role in CD8 ϩ T-cell homeostasis by promoting survival or proliferation of naive and memory phenotype CD8 T cells and in NK cell development, maturation, and survival (14,40,80). Notably, it has been reported that impaired IL-15 production is one of the mechanisms of the aberrant response of DC to IFN in HCV-infected patients (28).…”

Section: Discussionmentioning

confidence: 99%

Repression of Interferon Regulatory Factor 1 by Hepatitis C Virus Core Protein Results in Inhibition of Antiviral and Immunomodulatory Genes

Ciccaglione

Stellacci

Marcantonio

et al. 2007

J Virol

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Hepatitis C virus (HCV) proteins are known to interfere at several levels with both innate and adaptive responses of the host. A key target in these effects is the interferon (IFN) signaling pathway. While the effects of nonstructural proteins are well established, the role of structural proteins remains controversial. We investigated the effect of HCV structural proteins on the expression of interferon regulatory factor 1 (IRF-1), a secondary transcription factor of the IFN system responsible for inducing several key antiviral and immunomodulatory genes. We found substantial inhibition of IRF-1 expression in cells expressing the entire HCV replicon. Suppression of IRF-1 synthesis was mainly mediated by the core structural protein and occurred at the transcriptional level. The core protein in turn exerted a transcriptional repression of several interferonstimulated genes, targets of IRF-1, including interleukin-15 (IL-15), IL-12, and low-molecular-mass polypeptide 2. These data recapitulate in a unifying mechanism, i.e., repression of IRF-1 expression, many previously described pathogenetic effects of HCV core protein and suggest that HCV core-induced IRF-1 repression may play a pivotal role in establishing persistent infection by dampening an effective immune response.Infection with hepatitis C virus (HCV) represents the major cause of liver disease, affecting more than 170 million individuals worldwide (26). After a subclinical phase, more than 80% of patients progress to persistent HCV infection, which is the leading cause of chronic liver disease associated with cirrhosis and hepatocellular carcinoma (13). The persistence of the virus in the majority of infected individuals is linked to the ability of HCV to evade and/or antagonize the host immune response at both the local and systemic levels. Accordingly, although hepatocytes are a major target of HCV infection, the virus can also replicate in immune cells, including effector cells (1,11). In this respect, resistance to interferon (IFN) therapy is a hallmark of evolution in persistence, indicating that knocking down the antiviral and immunomodulating effects of IFN is a successful strategy for evading the host immune surveillance (21). The production and secretion of IFN type I is pivotal in inducing a global antiviral state through paracrine IFN production and the subsequent activation of interferon-stimulated genes (ISGs) within the infected cells and in the surrounding tissues (70). The role of IFN in HCV infection is thus crucial (21). Functional genomic analyses from cohorts of human subjects with chronic infection have shown that infection is associated with a gene expression profile marked by ISGs whose level of expression is related to different degrees of liver fibrosis and cirrhosis (67). Similarly, gene expression profiling has demonstrated that acute resolving infections in chimpanzees are associated with high levels of hepatic ISG expression (4).The single-stranded RNA genome of HCV is translated into a polypeptide precursor of 3,010 amino aci...

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Interleukin-15 and the regulation of lymphoid homeostasis

Cited by 64 publications

References 69 publications

Initial Antigen Encounter Programs CD8+ T Cells Competent to Develop into Memory Cells That Are Activated in an Antigen-Free, IL-7- and IL-15-Rich Environment

Initial Antigen Encounter Programs CD8+ T Cells Competent to Develop into Memory Cells That Are Activated in an Antigen-Free, IL-7- and IL-15-Rich Environment

Trans-presentation of interleukin-15 by interleukin-15 receptor alpha is dispensable for the pathogenesis of autoimmune type 1 diabetes

Repression of Interferon Regulatory Factor 1 by Hepatitis C Virus Core Protein Results in Inhibition of Antiviral and Immunomodulatory Genes

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