The influence of chronic alcohol consumption on invariant natural killer T cells

Faya Zhang

Chronic alcohol consumption increases the incidence of infectious diseases and multiple types of cancer and decreases the survival of cancer patients, which is associated with a compromised host immune system. Invariant natural killer T (iNKT) cells are an important population of immunoregulatory cells and play important roles in shaping immune response in infectious diseases and cancers. However, the knowledge of alcohol’s effects on iNKT cells is very limited. Using a well-established experimental mouse model, we found that alcohol consumption in the steady state increases iNKT cells in the thymus and liver, enhances iNKT cell proliferation, activation and maturation. Upon activation, iNKT cells exhibit a Th1-dominant cytokine profile, and enhance Th1 response evidenced by the enhanced activation of dendritic cells, NK, T, and B cells, which favors anti-tumor immunity. In addition, alcohol consumption increases the expression of chemokine receptor CXCR3 on iNKT cells in the thymus, which could be associated with increased thymic retention of iNKT cells. Moreover, alcohol consumption increases inhibitory receptor NKG2A-expressing iNKT cells, which could be a negative feedback mechanism to prevent iNKT cell over-activation. In contrast to the steady state, with tumor progression alcohol consumption accelerates iNKT cell anergy and switches iNKT cell cytokine profile from Th1-dominant to Th2-dominant, which favors tumor progression and decreases the survival of melanoma-bearing mice. In subsequent mechanistic studies, we show that alcohol consumption increases C16-alkenyl-LPE, an endogenous lipid antigen important for iNKT cell development, in the thymus. This finding supports our hypothesis that alcohol consumption influences iNKT cells by altering their endogenous lipid antigens in the thymus. We further show that TNF-α, but not IFN-γ, mediates the alcohol-induced increase of NKG2A+ iNKT in the thymus and spleen and the alcohol-induced increase of CXCR3+ iNKT in the thymus. In summary, chronic alcohol consumption enhances iNKT cell proliferation, activation and maturation via increasing endogenous lipid antigens, which not only enhances iNKT cell Th1 response and favors antitumor immunity, it also predisposes iNKT cells to accelerated immunosenescence. Crosstalk with melanoma, alcohol accelerates iNKT cells anergy and favors tumor progression. TNF-a may play the key role in alcohol-induced increase in CXCR3+ and NKG2A+ iNKT cells.

The influence of chronic alcohol consumption on invariant natural killer T cells

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