Stimulatory and costimulatory effects of IL-18 directed to different small intestinal CD43 T cell subsets

Montufar-Solis, Dina; Wang, Heuy-Ching; Klein, John R.

doi:10.1189/jlb.0207108

Cited by 7 publications

(5 citation statements)

References 52 publications

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“…There are differences between mouse and human immunology; human T cells are more responsive to IL-18 than mouse T cells. This might help explain why the in vitro effects of human IL-18 on T cells are more potent than those of mouse IL-18 ( Carroll et al, 2008 ; Montufar-Solis et al, 2007 ). Because of the immune deficiency of the NSG model and lack of a representative tumor microenvironment, further investigation is underway to comprehensively evaluate the safety of IL-18-CAR T cells, interaction with tumor infiltrating T and natural killer (NK) cells, and modulation of the tumor microenvironment in mice with intact host immune systems.…”

Section: Discussionmentioning

confidence: 99%

Augmentation of Antitumor Immunity by Human and Mouse CAR T Cells Secreting IL-18

et al. 2017

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SUMMARY The effects of transgenically encoded human and mouse IL-18 on T cell proliferation and its application in boosting chimeric antigen receptor (CAR) T cells are presented. Robust enhancement of proliferation of IL-18-secreting human T cells occurred in a xenograft model, and this was dependent on TCR and IL-18R signaling. IL-18 augmented IFN-γ secretion and proliferation of T cells activated by the endogenous TCR. TCR-deficient, human IL-18-expressing CD19 CAR T cells exhibited enhanced proliferation and antitumor activity in the xenograft model. Antigen-propelled activation of cytokine helper ensemble (APACHE) CAR T cells displayed inducible expression of IL-18 and enhanced antitumor immunity. In an intact mouse tumor model, CD19-IL-18 CAR T cells induced deeper B cell aplasia, significantly enhanced CAR T cell proliferation, and effectively augmented antitumor effects in mice with B16F10 melanoma. These findings point to a strategy to develop universal CAR T cells for patients with solid tumors.

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Section: Discussionmentioning

confidence: 99%

Augmentation of Antitumor Immunity by Human and Mouse CAR T Cells Secreting IL-18

et al. 2017

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“…Cells were stained using a protocol similar to that previously described by our laboratory (Montufar-Solis et al, 2007). Antibodies used were: purified anti-hamster IgG, purified anti-mouse CD3ε, FITC-control IgG, monensin intracellular protein block (BD Biosciences, San Jose, CA), FITC anti-mouse CD4, Alexafluor 660 anti-mouse IL-17A, PE anti-mouse RORγt, Alexafluor 647 IgG, PE IgG, and anti-mouse CD16/32 (eBioscience).…”

Section: Methodsmentioning

confidence: 99%

A role for IL-10 in the transcriptional regulation of Roquin-1

Schaefer¹,

Montufar-Solis²,

Klein³

2014

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Roquin-1, a RING finger E3 ubiquitin ligase, functions as a modulator of inflammation; however, nothing is known about how Rc3h1 expression is regulated. Here, we describe an opposing relationship between Roquin-1 and the IL-17 proinflammatory cytokine by demonstrating that enforced expression of Rc3h1 restricts Il17a expression, and that exposure of T cells to IL-10, a cytokine with immunosuppressive activity, increases Rc3h1 expression. Luciferase reporter assays conducted using eight transcription factor plasmids (STAT1, STAT3, STAT5, GATA2, c-Rel, IKZF1, IKZF2, and IKZF3) demonstrated that STAT1, STAT3, GATA2, and c-Rel increased Rc3h1 promoter activity, whereas IKZF2 decreased activity. Gene expression of those five transcription factors increased in T cells exposed to IL-10. Transcription factor-specific siRNAs suppressed the IL-10 effect on Rc3h1 transcription. These findings identify a role for IL-10 in regulating Rc3h1 transcription, and they have implications for understanding how Roquin-1 controls the immune response.

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“…siIELs were isolated using a protocol previously reported by our laboratory [9]. For isolation of siLPLs, the epithelial layer was first digested in DTT/EDTA [9], removed, and the remaining intestinal fragments were incubated in 50 ml of RPMI supplemented with 10% FBS, 0.36 mM CaCl 2 , 100U/ml of Collagenase IV (Sigma, St. Louis, MO) for 1 h at 37°C with stirring. Cells were filtered through nylon wool, collected, and centrifuged at 400 g through a 40%/70% Percoll gradient.…”

Section: Methodsmentioning

confidence: 99%

Small Intestine Inflammation in Roquin-Mutant and Roquin-Deficient Mice

et al. 2013

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Roquin, an E3 ubiquitin ligase that localizes to cytosolic RNA granules, is involved in regulating mRNA stability and translation. Mice that have a M199R mutation in the Roquin protein (referred to as sanroque or Roquinsan/san mice) develop autoimmune pathologies, although the extent to which these occur in the intestinal mucosa has not been determined. Here, we demonstrate that Roquinsan/san mice reproducibly develop intestinal inflammation in the small intestine but not the colon. Similarly, mice generated in our laboratory in which the Roquin gene was disrupted by insertion of a gene trap cassette (Roquingt/gt mice) had small intestinal inflammation that mimicked that of Roquinsan/san mice. MLN cells in Roquinsan/san mice consisted of activated proliferating T cells, and had increased numbers of CD44hi CD62Llo KLRG1+ short-lived effector cells. Proportionally more small intestinal intraepithelial lymphocytes in Roquinsan/san mice expressed the ICOS T cell activation marker. Of particular interest, small intestinal lamina propria lymphocytes in Roquinsan/san mice consisted of a high proportion of Gr-1+ T cells that included IL-17A+ cells and CD8+ IFN-γ+ cells. Extensive cytokine dysregulation resulting in both over-expression and under-expression of chemotactic cytokines occurred in the ileum of Roquinsan/san mice, the region most prone to the development of inflammation. These findings demonstrate that chronic inflammation ensues in the intestine following Roquin alteration either as a consequence of protein mutation or gene disruption, and they have implications for understanding how small intestinal inflammation is perpetuated in Crohn's disease (CD). Due to the paucity of animal models of CD-like pathophysiology in the small intestine, and because the primary gene/protein defects of the Roquin animal systems used here are well-defined, it will be possible to further elucidate the underlying genetic and molecular mechanisms that drive the disease process.

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Stimulatory and costimulatory effects of IL-18 directed to different small intestinal CD43 T cell subsets

Cited by 7 publications

References 52 publications

Augmentation of Antitumor Immunity by Human and Mouse CAR T Cells Secreting IL-18

Augmentation of Antitumor Immunity by Human and Mouse CAR T Cells Secreting IL-18

A role for IL-10 in the transcriptional regulation of Roquin-1

Small Intestine Inflammation in Roquin-Mutant and Roquin-Deficient Mice

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