Journal
CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
Volume 45, Issue 10, Pages 1002-1009Publisher
WILEY
DOI: 10.1111/1440-1681.12992
Keywords
colorectal cancer; lymphocyte activation gene 3; mucin-domain containing-3; Treg
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Regulatory T (Treg) cells are critical suppressors of inflammation and are thought to exert mainly deleterious effects in cancers. In colorectal cancer (CRC), Foxp3(+) Treg accumulation in tumors was associated with poor prognosis. Hence, we examined the circulating Treg cells in CRC patients. Compared to controls, CRC patients presented mild upregulations in CD4(+) CD25(+/hi) T cells and in the more canonical CD4(+)CD25(+/hi) Foxp3(+) Treg cells in peripheral blood mononuclear cells. Both of these Treg populations could be roughly divided into lymphocyte activation gene 3 negative T cell immunoglobulin and mucin-domain containing-3 negative (LAG3(-)TIM3(-)) and LAG3(+)TIM3(+) subsets. In CRC patients, the LAG3(+) TIM3(+) subset represented approximately half of CD4(+)CD25(+/hi) T cells and greater than 60% of CD4(+)CD25(+/hi) Foxp3(+) Treg cells, which was significantly more frequent than in healthy controls. Compared to the LAG3(-) TIM3(-) CD4(+) CD25(+/hi) T cells, the LAG3(+)TIM3(+) CD4(+)CD25(+/hi) T cells presented considerably higher transforming growth factor-beta and slightly higher interleukin (IL)-10 secretion, together with higher cytotoxic T-lymphocyte associated protein 4 and Foxp3 expression levels. Notably, macrophages following incubation with LAG3(-)TIM3(-) CD4(+) CD25(+/hi) T cells and LAG3(+) TIM3(+) CD4(+)CD25(+/hi) T cells displayed different characteristics. Macrophages incubated with LAG3(+) TIM3(+) CD4(+)CD25(+/hi) T cells presented lower expression of major histocompatibility complex class II, CD80, CD86, and tumor necrosis factor-alpha but higher expression of IL-10, than macrophages incubated with LAG3(-)TIM3(-) CD4(+)CD25(+/hi) T cells. Together, our investigations demonstrated that CRC patients presented an enrichment of circulating Treg cells, in which the LAG3(+)TIM3(+) subset exhibited more potent expression of inhibitory molecules, and furthermore, the LAG3(+) TIM3(+) Treg cells could suppress the proinflammatory activation of macrophages more potently than the LAG3(-)TIM3(-) Treg cells.
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