The γc Family of Cytokines: Basic Biology to Therapeutic Ramifications

Leonard, Warren J.; Lin, Jian-Xin; O’Shea, John J.

doi:10.1016/j.immuni.2019.03.028

Cited by 248 publications

(195 citation statements)

References 265 publications

(281 reference statements)

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“…However, it is noteworthy that a minority of patients do not require IgG replacement therapy, suggesting that a few nondetectable transduced B cells are active (Hacein-Bey-Abina et al, 2010, 2014; Gaspar et al, 2011). The fact that IL15 is critical for NK cell differentiation explains why γc deficiency leads to a complete absence of this cell type (Leonard et al, 2019). NK cells reached control values in half of the patients within the first year after treatment; thereafter, however, very few NK cells persisted in the blood (Hacein-Bey-Abina et al, 2010, 2014).…”

Section: Additional and Serendipitous Findingsmentioning

confidence: 99%

Gene therapy for severe combined immunodeficiencies and beyond

Fischer

Hacein‐Bey‐Abina

2019

Journal of Experimental Medicine

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Ex vivo retrovirally mediated gene therapy has been shown within the last 20 yr to correct the T cell immunodeficiency caused by γc-deficiency (SCID X1) and adenosine deaminase (ADA) deficiency. The rationale was brought up by the observation of the revertant of SCIDX1 and ADA deficiency as a kind of natural gene therapy. Nevertheless, the first attempts of gene therapy for SCID X1 were associated with insertional mutagenesis causing leukemia, because the viral enhancer induced transactivation of oncogenes. Removal of this element and use of a promoter instead led to safer but still efficacious gene therapy. It was observed that a fully diversified T cell repertoire could be generated by a limited set (<1,000) of progenitor cells. Further advances in gene transfer technology, including the use of lentiviral vectors, has led to success in the treatment of Wiskott–Aldrich syndrome, while further applications are pending. Genome editing of the mutated gene may be envisaged as an alternative strategy to treat SCID diseases.

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Section: Additional and Serendipitous Findingsmentioning

confidence: 99%

Gene therapy for severe combined immunodeficiencies and beyond

Fischer

Hacein‐Bey‐Abina

2019

Journal of Experimental Medicine

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“…The STAT5 pathway is predominantly activated in T cells by members of the γc cytokine family (IL-2, -7, -9 and -15) (reviewed in [46]). These cytokines signal through receptors containing the γc (CD132) subunit and lead to the activation of the JAK3 tyrosine kinase.…”

Section: Stat5 In the Adaptive T Cell Responsesmentioning

confidence: 99%

“…Several cytokines/cytokine receptors trigger STAT3 signaling in T cells, including IL-6-type cytokines (IL-6 and Oncostatin M), IL-10, IL-17, IL-21 and IL-27. Among the STAT3-activating cytokines, IL-21 is peculiar: While its receptor contains the γc (CD132) subunit, signals downstream of IL-21R converge on STAT3 and to a lesser extent on STAT1, rather than on STAT5 activation [46]. Intriguingly, IL-21 was shown to promote in vitro proliferation of CD8 T naïve and memory cells in synergy with STAT5-inducing cytokines IL-7/IL-15 [90].…”

Section: Role Of Stat3 In T Cellsmentioning

confidence: 99%

Targeting STAT3 and STAT5 in Tumor-Associated Immune Cells to Improve Immunotherapy

Verdeil

Lawrence

Schmitt-Verhulst

et al. 2019

Cancers

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Oncogene-induced STAT3-activation is central to tumor progression by promoting cancer cell expression of pro-angiogenic and immunosuppressive factors. STAT3 is also activated in infiltrating immune cells including tumor-associated macrophages (TAM) amplifying immune suppression. Consequently, STAT3 is considered as a target for cancer therapy. However, its interplay with other STAT-family members or transcription factors such as NF-κB has to be considered in light of their concerted regulation of immune-related genes. Here, we discuss new attempts at re-educating immune suppressive tumor-associated macrophages towards a CD8 T cell supporting profile, with an emphasis on the role of STAT transcription factors on TAM functional programs. Recent clinical trials using JAK/STAT inhibitors highlighted the negative effects of these molecules on the maintenance and function of effector/memory T cells. Concerted regulation of STAT3 and STAT5 activation in CD8 T effector and memory cells has been shown to impact their tumor-specific responses including intra-tumor accumulation, long-term survival, cytotoxic activity and resistance toward tumor-derived immune suppression. Interestingly, as an escape mechanism, melanoma cells were reported to impede STAT5 nuclear translocation in both CD8 T cells and NK cells. Ours and others results will be discussed in the perspective of new developments in engineered T cell-based adoptive therapies to treat cancer patients. function of tumor-associated macrophages (TAM) and (ii) for the regulation of T cell functions. As STAT TFs are key players in the regulation of functions of these immune cells, their manipulation can have a beneficial or detrimental effect on the anti-tumor response depending on the targeted cell type. Tumor-Induced Inflammation Drives Accumulation of Tumor-Infiltrating Myeloid CellsCytokine receptor-induced signaling sustains and amplifies the activation of STAT3, NF-κB and AP-1 in a positive amplification loop, fueling tumor-associated inflammation. As such, a core inflammation-related gene set regulated by STAT3, NF-κB and AP-1 has recently been proposed as an "inflammatory index" in breast cancer cell lines and patient samples [4]. Importantly, in correlation with this inflammatory index, this study reported a concerted regulation of (i) non-inflammatory genes related to angiogenesis, metastasis, and cell proliferation; (ii) tumor genome instability; and (iii) heterogeneity of the tumor microenvironment (TME), including the recruited immune cells. Remarkably, these co-regulated characteristics were found across several cancer types driven by distinct oncogenes [4].Tumor-derived cytokines have been linked to the accumulation of immune-suppressive myeloid cells including both myeloid-derived suppressor cells (MDSCs; IMCs) and tumor-associated macrophages (TAM). In both human and mouse melanomas, IMCs have an important role in malignant progression and evasion from anti-tumor immunity that is linked to the suppression of T cell responses [6][7][8][9]. While increased...

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“…By nature of this combinatorial biology, mutations in the common chain have detrimental consequences, since they affect signaling of multiple cytokines. Genetic defects in IL2RG cause X-linked severe combined immunodeficiency due to defects in the entire IL-2 cytokine family (Leonard et al, 2019;Liao et al, 2011), and mutations in IL10RB result in infantile-onset inflammatory bowel disease, largely due to defective IL-10 signaling, while also associated with defective IL-22, IL-26, and IL-28 signaling (Ouyang and O'Garra, 2019).…”

Section: Intronic Variant C1699+4a>g Gp130 Leads To Loss Of Functionmentioning

confidence: 99%

Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome

Chen

Grigelioniené

Newton

et al. 2020

Journal of Experimental Medicine

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The gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines. Previous studies have identified cytokine-selective IL6ST defects that preserve LIF signaling. We describe three unrelated families with at least five affected individuals who presented with lethal Stüve-Wiedemann–like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping). Functional tests showed absent cellular responses to GP130-dependent cytokines including IL-6, IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF). Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect. This study identifies a new genetic syndrome caused by the complete lack of signaling of a whole family of GP130-dependent cytokines in humans and highlights the importance of the LIF signaling pathway in pre- and perinatal development.

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The γc Family of Cytokines: Basic Biology to Therapeutic Ramifications

Cited by 248 publications

References 265 publications

Gene therapy for severe combined immunodeficiencies and beyond

Gene therapy for severe combined immunodeficiencies and beyond

Targeting STAT3 and STAT5 in Tumor-Associated Immune Cells to Improve Immunotherapy

Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome

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