Decreased CXCR3 expression in CD4+ T cells exposed to asbestos or derived from asbestos-exposed patients

Our plain-English summary of Decreased CXCR3 expression in CD4+ T cells exposed to asbestos or derived from asbestos-exposed patients, by M. Maeda, Y. Nishimura, H. Hayashi, et al (American Journal of Respiratory Cell and Molecular Biology, 2011).

The study

• Authors: M. Maeda, Y. Nishimura, H. Hayashi, N. Kumagai, Y. Chen, S. Murakami, Y. Miura, J. Hiratsuka, T. Kishimoto, T. Otsuki
• Journal: American Journal of Respiratory Cell and Molecular Biology
• Published: 2011;45(4):795-803
• Cited by: 30 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Asbestos causes malignant tumors such as lung cancer and malignant mesothelioma (MM). To determine whether asbestos exposure causes reduction of antitumor immunity, we established an in vitro T-cell line model of low-dose and continuous exposure to asbestos using an human adult T-cell leukemia virus-1 immortalized human polyclonal T-cell line, MT-2, and revealed that MT-2 cells exposed continuously to asbestos showed resistance to asbestos-induced apoptosis. In addition, the cells presented reduction of surface CXCR3 chemokine receptor expression and IFN-γ production. In this study, to confirm that these findings are suitable for clinical translation, surface CXCR3 and IFN-γ expression were analyzed using freshly isolated human CD4(+) T cells derived from healthy donors and patients with pleural plaque (PP) or MM. The results revealed that CXCR3 and IFN-γ expression in the ex vivo model were reduced in some cases. Additionally, CXCR3 expression in CD4(+) T cells from PPs and MMs was significantly reduced compared with that from healthy donors, and CD4(+) T cells from patients with MMs exhibited a marked reduction in IFN-γ mRNA levels after stimulation in vitro. Moreover, CD4(+)CXCR3(+) T cells in lymphocytes from MMs showed a tendency for an inverse correlation with its ligand CXCL10/IP10 in plasma. These findings show reduction of antitumor immune function in asbestos-exposed patients and indicate that CXCR3, IFN-γ, and CXCL10/IP10 may be candidates to detect and monitor disease status.

In plain English

This Japanese laboratory study combined an ex vivo chrysotile experiment with blood analyses from asbestos-exposed patients. Stimulated CD4+ T cells from healthy donors were cultured with chrysotile-B at doses printed as 2 to 10 mg/cm2. In a representative example, surface CXCR3 fell with increasing dose after 40 days. Across six donors at 10 mg/cm2, CXCR3 was significantly reduced at 28 days, though the authors noted this depended largely on one case; CCR5 showed no significant change. In three donors whose CXCR3 had fallen, IFN-gamma mRNA (P = 0.3226) and IFN-gamma-positive cells (P = 0.0511) fell or tended to fall, neither significantly. In 19 healthy donors, 13 pleural plaque patients and 8 malignant mesothelioma patients, CXCR3 on CD4+ T cells was significantly lower in both patient groups; CCR5 did not differ. The patient groups were older (mean 71.5 and 67.4 years versus 42.3); 13 younger and 6 older healthy donors did not differ significantly in CXCR3. In stimulated CD4+ T cells, IFN-gamma mRNA was significantly reduced only in mesothelioma, and IL-6 in culture supernatants was higher in both patient groups.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: ex vivo culture experiment on human CD4+ T cells exposed to chrysotile, plus cross-sectional comparison of blood samples from healthy donors and patients with pleural plaque or malignant mesothelioma
• Who was studied: Ex vivo experiment: CD4+ T cells from 6 healthy donors (mean age 34.8, range 25-50; 3 men, 3 women). Patient analysis: 19 healthy donors (mean age 42.3), 13 patients with pleural plaque (mean age 71.5), 8 with malignant mesothelioma (mean age 67.4); mRNA and cytokine analyses in 13 healthy donors, 13 pleural plaque, 7 mesothelioma; plasma CXCL10 in 10, 8 and 8. Kawasaki Medical School and Okayama Rosai Hospital, Japan.
• Exposure: In culture: chrysotile-B at doses printed as 2 to 10 mg/cm2 (the six-donor comparison used 10 mg/cm2 for 7 and 28 days; a representative dose-response example ran 40 days). In patients: past asbestos exposure, as indicated by pleural plaque or malignant mesothelioma.
• Main results:
  • In a representative example of cultured CD4+ T cells from a healthy donor, surface CXCR3 decreased with increasing chrysotile-B dose (2 to 10 mg/cm2 as printed) after 40 days
  • The comparison across all six healthy donors used 10 mg/cm2 chrysotile-B for 7 and 28 days
  • Across the six donors, CXCR3 was significantly reduced after 28 days at 10 mg/cm2, but the authors noted the difference appeared to depend on one case
  • CCR5 expression in cultured CD4+ T cells varied among donors and showed no significant change after 7 or 28 days of chrysotile-B exposure
  • The IFN-gamma analysis used donors who had shown decreased surface CXCR3 after chrysotile-B exposure
  • In these three donors, IFN-gamma mRNA fell in all three after 28 days of exposure without statistical significance (P = 0.3226), and IFN-gamma-positive cells tended to fall (P = 0.0511)
  • In patients, the percentage of CD4+CXCR3+ T cells in lymphocytes was significantly lower in pleural plaque and mesothelioma than in healthy donors, with mesothelioma lowest; CD4+CCR5+ percentages did not differ
  • CXCR3 expression in CD4+ T cells was significantly lower in pleural plaque and mesothelioma patients than in healthy donors; CCR5 expression did not differ
  • Among healthy donors, younger (n = 13) and older (n = 6) groups did not differ significantly in CD4+CXCR3+ percentage or CXCR3 expression
  • IFN-gamma mRNA in stimulated CD4+ T cells was significantly decreased only in the mesothelioma group compared with healthy donors and pleural plaque
  • No significant correlation was found between CXCR3 expression and IFN-gamma mRNA in any of the three groups
  • Secreted IFN-gamma in supernatants from cultured CD4+ T cells did not differ significantly between groups
  • In supernatants from cultured, stimulated CD4+ T cells, IL-6 was significantly higher in pleural plaque and mesothelioma than in healthy donors
  • Plasma CXCL10/IP10 tended to be higher in pleural plaque and mesothelioma than in healthy donors, without significant difference
  • Correlation between CD4+CXCR3+ percentage and plasma CXCL10/IP10 was not significant in any group, with an inverse tendency in mesothelioma (P = 0.081)
• The authors' conclusion: The authors concluded that reduction of CXCR3 expression in human peripheral CD4+ T cells occurred after chronic chrysotile exposure, suggesting antitumour immunity might not function normally in patients with asbestos-related disease, and that IFN-gamma suppression appeared linked to the occurrence of mesothelioma rather than to asbestos exposure itself.
• Limitations the authors state:
  • The ex vivo model could not reproduce months-long exposure because IL-2-dependent proliferation of CD4+ T cells is not permanent, limiting culture to several weeks
  • The number of cases used in the ex vivo intracellular IFN-gamma experiment was small
  • The significant CXCR3 reduction at 28 days appeared to be driven by one case
  • The authors noted the significantly higher IL-4 concentration in mesothelioma might be too low to have physiological function

Topics

The National Library of Medicine indexes this study under subjects our site covers: Asbestosis, Chrysotile, Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Lung Cancer, Malignant Mesothelioma, Asbestos Exposure, Apoptosis, Pleural Plaques.

Related studies

• Reduction of CXC chemokine receptor 3 in an in vitro model of continuous exposure to asbestos in a human T-cell line, MT-2 — M. Maeda, Y. Nishimura, et al. (2011)
• Alteration of cytoskeletal molecules in a human T cell line caused by continuous exposure to chrysotile asbestos — M. Maeda, Y. Chen, et al. (2013)
• Decrease in phosphorylation of ERK following decreased expression of NK cell-activating receptors in human NK cell line exposed to asbestos — Y. Nishimura, M. Maeda, et al. (2009)
• Ingredients such as trehalose and hesperidin taken as supplements or foods reverse alterations in human T cells, reducing asbestos exposure-induced antitumor immunity — S. Yamamoto, S. Lee, et al. (2021)
• Accelerated cell cycle progression of human regulatory T cell-like cell line caused by continuous exposure to asbestos fibers — S. Lee, H. Matsuzaki, et al. (2017)
• Enhancement of regulatory T cell-like suppressive function in MT-2 by long-term and low-dose exposure to asbestos — C. Ying, M. Maeda, et al. (2015)

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