Abstract
BackgroundAsbestos fibers possess tumorigenicity and are thought to cause mesothelioma. We have previously reported that exposure to asbestos fibers causes a reduction in antitumor immunity. Asbestos exposure in the mixed lymphocyte reaction (MLR) showed suppressed induction of cytotoxic T lymphocytes (CTLs), accompanied by a decrease in proliferation of CD8+ T cells. Recently, we reported that asbestos-induced suppression of CTL induction is not due to insufficient levels of interleukin-2 (IL-2). In this study, we continue to investigate the mechanism responsible for the effect of asbestos fibers on the differentiation of CTLs and focus on interleukin-15 (IL-15) which is known to be a regulator of T lymphocyte proliferation.MethodsFor MLR, human peripheral blood mononuclear cells (PBMCs) were cultured with irradiated allogenic PBMCs upon exposure to chrysotile B asbestos at 5 μg/ml for 7 days. After 2 days of culture, IL-15 was added at 1 ng/ml. After 7 days of MLR, PBMCs were collected and analyzed for phenotypic and functional markers of CD8+ T cells with fluorescence-labeled anti-CD3, anti-CD8, anti-CD45RA, anti-CD45RO, anti-CD25, and anti-granzyme B antibodies using flow cytometry. To examine the effect of IL-15 on the expression level of intracellular granzyme B in proliferating and non-proliferating CD8+ lymphocytes, PBMCs were stained using carboxyfluorescein diacetate succinimidyl ester (CFSE) and then washed and used for the MLR.ResultsIL-15 addition partially reversed the decrease in CD3+CD8+ cell numbers and facilitated complete recovery of granzyme B+ cell percentages. IL-15 completely reversed the asbestos-induced decrease in percentage of granzyme B+ cells in both non-proliferating CFSE-positive and proliferating CFSE-negative CD8+ cells. The asbestos-induced decrease in the percentage of CD25+ and CD45RO+ cells in CD8+ lymphocytes was not reversed by IL-15.ConclusionThese findings indicate that CTLs induced upon exposure to asbestos possess dysfunctional machinery that can be partly compensated by IL-15 supplementation, and that IL-15 is more effective in the recovery of proliferation and granzyme B levels from asbestos-induced suppression of CTL induction compared with IL-2.
Highlights
Asbestos fibers possess tumorigenicity and are thought to cause mesothelioma
B–d, exposure to chrysotile B (CB) tended to result in a decrease in the percentage of carboxyfluorescein diacetate succinimidyl ester (CFSE)-negative and granzyme B-positive cells (p = 0.062), the CFSE-positive and granzyme B-positive cells in CD8+ lymphocytes did not decrease following exposure to CB. The percentage of both proliferating and non-proliferating granzyme B-positive cells upon asbestos exposure increased significantly following the addition of IL-15. These results indicate that exogenously added IL-15 led to partial recovery of the asbestosinduced suppression of cell proliferation, and restored and enhanced intracellular granzyme B in both proliferating and non-proliferating CD8+ lymphocytes exposed to asbestos
The present study demonstrated that cytotoxic T lymphocytes (CTLs) induced upon exposure to asbestos possess dysfunctional machinery that can be partly compensated by IL-15 supplementation
Summary
We have previously reported that exposure to asbestos fibers causes a reduction in antitumor immunity. We reported that asbestos-induced suppression of CTL induction is not due to insufficient levels of interleukin-2 (IL-2). The use of asbestos has been prohibited in 55 countries, these prohibitions have only recently been enacted and have not yet had a measureable impact on the incidence of asbestos-related diseases. In the USA, despite the decrease in age-adjusted mesothelioma incidence rates in the past decades, approximately 3000 incident cases of mesothelioma are registered each year. The overall number of new cases and of deaths per year caused by mesothelioma continues to steadily increase in many countries where populations are becoming older since mesothelioma affects mostly older people. The highest age-standardized incidence rates in 2018 were observed in the USA, Australia, Russia, Western Europe, Turkey, South Africa, and Argentina according to the World Health Organization [5]
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