Tissue Cytokine IL-33 Modulates the Cytotoxic CD8 T Lymphocyte Activity During Nutrient Deprivation by Regulation of Lineage-Specific Differentiation Programs

Dreis, Caroline; Ottenlinger, Florian; Putyrski, Mateusz; Ernst, Andreas; Huhn, Meik; Schmidt, Karl‐Hermann; Pfeilschifter, Josef; Radeke, Heinfried H.

doi:10.3389/fimmu.2019.01698

Cited by 13 publications

(20 citation statements)

References 62 publications

(60 reference statements)

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“…First, the bioactivity of IL-33 is limited in blood [33]. A study measured the serum levels of IL-33 in 30 healthy controls and found that all of the samples were undetectable (lowest limit of detection, 75 pg/mL) [33]. Future study addressing the role of IL-33 in AD can simultaneously measure IL-33 and its receptor ST2.…”

Section: Limitationsmentioning

confidence: 99%

The role of interleukin-33 in patients with mild cognitive impairment and Alzheimer’s disease

Liang

Tsai

et al. 2020

Alz Res Therapy

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Background: The neuroprotective role of interleukin (IL)-33 is supported by numerous preclinical studies, but it remains uninvestigated in clinical studies of Alzheimer's disease (AD). We aimed to examine the association between human blood levels of IL-33 and cognitive preservation in amnestic mild cognitive impairment (aMCI) and AD. Methods: A total of 100 participants (26 controls, 35 aMCI patients, and 39 AD patients) completed two Mini-Mental State Examinations (MMSEs) over a 1-year interval. In all 100 participants at the second MMSE, we examined the plasma levels of IL-33, IL-β, IL-1 receptor agonist (IL-1RA), beta amyloid (Aβ), and tau and apolipoprotein E (ApoE) genotyping; we also performed Hopkins Verbal Learning Test, Trail Making Test, forward and backward digit span, and Clinical Dementia Rating. Results: IL-33 expression showed a positive trend among controls (1/26 = 3.8%), aMCI (9/35 = 25.7%), and AD (17/39 = 43.6%) (trend analysis: P < 0.001). Patients expressing IL-33 preserved their cognitive function compared with IL-33 nonexpressing patients (1-year ΔMMSE, 0.16 ± 1.6 vs − 1.5 ± 2.6; P = 0.006). The cognitive preservation was not associated with the lower levels of Aβ, tau, and ApoE ε4, while higher levels of ApoE ε4 and phosphorylated tau were indeed associated with cognitive decline. The aMCI patients with AD conversion during study period had higher proportion of IL-33(−) than non-AD converters (90.9% vs 53.3%, P = 0.04). Conclusions: IL-33 or its associated signaling pathways may represent a new treatment paradigm for aMCI and AD.

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Section: Limitationsmentioning

confidence: 99%

The role of interleukin-33 in patients with mild cognitive impairment and Alzheimer’s disease

Liang

Tsai

et al. 2020

Alz Res Therapy

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“…Alongside T cell receptor (TCR) signaling and IL-2 stimulation, IL-12 is described as the “third signal” for the expansion of cytotoxic T c 1 immune cell responses. One focus of our recent report was to understand the role of IL-33 and IL-12 in CD8 + T lymphocyte differentiation under nutrient deprivation ( 28 ). The function of IL-33 is dependent not only on TCR signaling, but also on the presence of IL-12.…”

Section: Introductionmentioning

confidence: 99%

Enhanced CXCR4 Expression of Human CD8Low T Lymphocytes Is Driven by S1P4

et al. 2021

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Although the human immune response to cancer is naturally potent, it can be severely disrupted as a result of an immunosuppressive tumor microenvironment. Infiltrating regulatory T lymphocytes contribute to this immunosuppression by inhibiting proliferation of cytotoxic CD8+ T lymphocytes, which are key to an effective anti-cancer immune response. Other important contributory factors are thought to include metabolic stress caused by the local nutrient deprivation common to many solid tumors. Interleukin-33 (IL-33), an alarmin released in reaction to cell damage, and sphingosine-1-phosphate (S1P) are known to control cell positioning and differentiation of T lymphocytes. In an in vitro model of nutrient deprivation, we investigated the influence of IL-33 and S1P receptor 4 (S1P4) on the differentiation and migration of human CD8+ T lymphocytes. Serum starvation of CD8+ T lymphocytes induced a subset of CD8Low and IL-33 receptor-positive (ST2L+) cells characterized by enhanced expression of the regulatory T cell markers CD38 and CD39. Both S1P1 and S1P4 were transcriptionally regulated after stimulation with IL-33. Moreover, expression of the chemokine receptor CXCR4 was increased in CD8+ T lymphocytes treated with the selective S1P4 receptor agonist CYM50308. We conclude that nutrient deprivation promotes CD8Low T lymphocytes, contributing to an immunosuppressive microenvironment and a poor anti-cancer immune response by limiting cytotoxic effector functions. Our results suggest that S1P4 signaling modulation may be a promising target for anti-CXCR4 cancer immunotherapy.

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“…Our study has limitations. First, the bioactivity of IL-33 is limited in blood [28]. A study measured the serum levels of IL-33 in 30 healthy controls and found that all of the samples were undetectable (lowest limit of detection: 75 pg/ml).…”

Section: Discussionmentioning

confidence: 99%

The Role of Interleukin-33 in Patients with Mild Cognitive Impairment and Alzheimer's Disease

Liang

Tsai

et al. 2020

SSRN Journal

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Background: The neuroprotective role of Interleukin (IL)-33 is supported in numerous pre-clinical studies but remains mostly uninvestigated in clinical studies of Alzheimer's disease (AD). We aimed to examine the association between human blood levels of IL-33 and cognitive preservation in amnestic mild cognitive impairment (aMCI) and AD. Methods: A total of 100 participants (26 controls, 35 aMCI patients, and 39 AD patients) were completed twice Mini Mental State Examination (MMSE) over a 1-year interval. At the second MMSE, the 100 participants examined the plasma levels of IL-33, IL-β, IL-1 receptor agonist (IL-1RA), beta amyloid (Aβ), and tau and apolipoprotein E (ApoE) genotyping, and Hopkins Verbal Learning Test, Trail Making Test, forward and backward digit span, and Clinical Dementia Rating were performed as well. Results: IL-33 expression showed a positive trend among controls (1/26 = 3.8%), aMCI (9/35 = 25.7%), and AD (17/39 = 43.6%) (trend analysis: P < 0.001). The patients expressing IL-33 preserved their cognitive function compared with IL-33 non-expressing patients (1-year ΔMMSE: 0.16 ± 1.6 vs-1.5 ± 2.6; P = 0.006). The cognitive preservation was not associated with the lower levels of Aβ, tau, and AopE ε4, while higher levels of AopE ε4 and phosphorylated tau were indeed associated with cognitive decline. The aMCI patients with AD conversion during study period had higher proportion of IL-33(-) than non-AD converters (0.9% vs 53.3%, P = 0.04). Conclusions: IL-33 or its associated signaling pathways may represent a new treatment paradigm for aMCI and AD.

show abstract

Tissue Cytokine IL-33 Modulates the Cytotoxic CD8 T Lymphocyte Activity During Nutrient Deprivation by Regulation of Lineage-Specific Differentiation Programs

Cited by 13 publications

References 62 publications

The role of interleukin-33 in patients with mild cognitive impairment and Alzheimer’s disease

The role of interleukin-33 in patients with mild cognitive impairment and Alzheimer’s disease

Enhanced CXCR4 Expression of Human CD8Low T Lymphocytes Is Driven by S1P4

The Role of Interleukin-33 in Patients with Mild Cognitive Impairment and Alzheimer's Disease

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