STAT3 promotes CD1d‐mediated lipid antigen presentation by regulating a critical gene in glycosphingolipid biosynthesis

Iyer, Abhirami K.; Liu, Jianyun; Gallo, Richard M.; Kaplan, Mark H.; Brutkiewicz, Randy R.

doi:10.1111/imm.12521

Cited by 12 publications

(14 citation statements)

References 67 publications

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“…Iyer et al demonstrated that STAT3 inhibition reduced endogenous lipid antigen presentation to NKT cells [50]. Knockdown of STAT3 led to decreased levels of uridine diphosphate (UDP) glucose ceramide glucosyltransferase, an enzyme involved in glycosphingolipid biosynthesis [50]. Moreover, CD1D levels of HEK-293 cells containing STAT3 knockdown were not deemed significantly different [50].…”

Section: Discussionmentioning

confidence: 99%

“…Knockdown of STAT3 led to decreased levels of uridine diphosphate (UDP) glucose ceramide glucosyltransferase, an enzyme involved in glycosphingolipid biosynthesis [50]. Moreover, CD1D levels of HEK-293 cells containing STAT3 knockdown were not deemed significantly different [50]. However, it must be noted these studies used CD1d transfectants; thus, CD1d was not regulated by its natural, endogenous promoter.…”

Section: Discussionmentioning

confidence: 99%

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Histone deacetylase inhibitors enhance CD1d-dependent NKT cell responses to lymphoma

Tiper

Webb

2016

Cancer Immunol Immunother

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Histone deacetylases (HDACs) are a family of enzymes that influence expression of genes implicated in tumor initiation, progression and anti-tumor responses. In addition to their canonical role in deacetylation of histones, HDACs regulate many non-canonical targets, such as Signal Transducer and Activator of Transcription 3 (STAT3). We hypothesize that tumors use epigenetic mechanisms to dysregulate CD1d-mediated antigen presentation, thereby impairing the ability of natural killer T (NKT) cells to recognize and destroy malignant cells. In this study, we pre-treated CD1d-expressing tumor cells with HDAC inhibitors (HDACi) and assessed CD1D-dependent NKT cell responses to mantle cell lymphoma (MCL). Pre-treatment with Trichostatin A, a pan-HDACi, rapidly enhanced both CD1d- and MHC class II-mediated antigen presentation. Similarly, treatment of MCL cells with other HDACi resulted in enhanced CD1d-dependent NKT cell responses. The observed changes are due, at least in part, to an increase in both CD1D mRNA and CD1D cell surface expression. Mechanistically, we found that HDAC2 binds to the CD1D promoter. Knockdown of HDAC2 in tumor cells resulted in a significant increase in CD1D-mediated antigen presentation. In addition, treatment with HDACi inhibited STAT3 and STAT3-regulated inflammatory cytokine secretion by MCL cells. We demonstrated that MCL-secreted IL-10 inhibits CD1d-mediated antigen presentation and pretreatment with TSA abrogates secretion of IL-10 by MCL. Taken together, our studies demonstrate the efficacy of HDACi in restoring anti-tumor responses to MCL through both cell-intrinsic and extrinsic mechanisms and strongly implicate a role for HDACi in enhancing immune responses to cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibitors enhance CD1d-dependent NKT cell responses to lymphoma

Tiper

Webb

2016

Cancer Immunol Immunother

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“…Interestingly, we found that ROCK actually promoted Ag presentation by MHC class II molecules (101). This was another example in which we have found specific cell signaling pathways that differentially regulate Ag presentation by MHC class II vs. CD1d (21, 96, 101). …”

Section: Introduction Of Cell Signaling Pathwaysmentioning

confidence: 95%

“…Here, crosslinking CD1d on colonic epithelial cells results in STAT3 activation; the transcription of the il-10 gene (by STAT3) and consequent IL-10 production controls inflammation in those cells (95). Recently, we showed that STAT3 is essential for CD1d-mediated Ag presentation, due to its ability to regulate the transcription of UDP glucose ceramide glycosyltransferase, an enzyme involved in the first step of glycosphingolipid biosynthesis—from which the natural ligands of CD1d are derived (96). The critical nature of STAT3 in the CD1d/NKT cell axis is evident in patients with loss-of-function mutations in STAT3.…”

Section: Introduction Of Cell Signaling Pathwaysmentioning

confidence: 99%

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Cell Signaling Pathways That Regulate Antigen Presentation

Brutkiewicz

2016

The Journal of Immunology

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Cell signaling pathways regulate much in the life of a cell: from shuttling cargo through intracellular compartments and onto the cell surface, how it should respond to stress, protecting itself from harm (environmental insults or infections), to ultimately, death by apoptosis. These signaling pathways are important for various aspects of the immune response as well. However, not much is known in terms of the participation of cell signaling pathways in Ag presentation--a necessary first step in the activation of innate and adaptive T cells. In this brief review, I will discuss the known signaling molecules (and pathways) that regulate how Ags are presented to T cells and the mechanism(s) if identified. Studies in this area have important implications in vaccine development and new treatment paradigms against infectious diseases, autoimmunity and cancer.

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CX3CR1‐Expressing Myeloid Cells Regulate Host–Helminth Interaction and Lung Inflammation

et al. 2022

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the occurrence of reinfection after drug treatment, [3] understanding how to trigger protective immune effector responses offers valuable therapeutic insight to promote helminth elimination by the host. Helminths are macroparasites with complex life cycles that frequently involve tissue migration through many organs, leading to tissue pathology and inflammation. [4] Immune effector responses at these sites of incoming larval parasites are especially critical in preventing longterm infections. In particular, the lung is a main infection site for many helminths, including hookworms Necator americanus and Ancylostoma duodenale, where the infectious larvae migrate through the lung as an essential developmental step before reaching the small intestine. [5] While clinical symptoms of pulmonary helminth infection in humans have been reported, including coughing, wheezing, and potentially respiratory failure, investigation of the immune-mediated mechanisms within the lung against the helminth are less well understood, and rely on in vivo models such as murine helminth infection. One such murine model is infection with Nippostrongylus brasiliensis, a natural helminth parasite of rodents, which has a transient migratory phase through the lung prior to reaching the small intestine, mimicking pulmonary hookworm infection. [6] Previous studies have shown that pulmonary immune responses, including neutrophils and macrophages, are critical against Nippostrongylus. [7,8] These studies utilized secondary challenge with Nippostrongylus to show that CD4 + derived T helper type 2 cytokines and neutrophils promoted lung macrophage interaction and killing of Nippostrongylus larval parasites. The importance of other innate cells such as eosinophils has also been investigated, showing modest effects of eosinophils in promoting secondary effector responses to Nippostrongylus. [9] Eosinophil-dependent resistance was not required for resistance to the primary infection but was necessary for resistance to the secondary infection, which involves immobilizing worms and inhibiting their progression to the gut. These studies highlight the importance of innate effector cells in the lung, and prompted our study to investigate innate cells in Nippostrongylus infection. We focused on lung monocytes, which have been less well studied in Many helminth life cycles, including hookworm, involve a mandatory lung phase, where myeloid and granulocyte subsets interact with the helminth and respond to infection-induced lung injury. To evaluate these innate subsets in Nippostrongylus brasiliensis infection, reporter mice for myeloid cells (CX3CR1 GFP ) and granulocytes (PGRP dsRED ) are employed. Nippostrongylus infection induces lung infiltration of reporter cells, including CX3CR1 + myeloid cells and PGRP + eosinophils. Strikingly, CX3CR1 GFP/GFP mice, which are deficient in CX3CR1, are protected from Nippostrongylus infection with reduced weight loss, lung leukocyte infiltration, and worm burden compared to CX3CR1 +/+ mice. This protective effect is spec...

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STAT3 promotes CD1d‐mediated lipid antigen presentation by regulating a critical gene in glycosphingolipid biosynthesis

Cited by 12 publications

References 67 publications

Histone deacetylase inhibitors enhance CD1d-dependent NKT cell responses to lymphoma

Histone deacetylase inhibitors enhance CD1d-dependent NKT cell responses to lymphoma

Cell Signaling Pathways That Regulate Antigen Presentation

CX3CR1‐Expressing Myeloid Cells Regulate Host–Helminth Interaction and Lung Inflammation

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