Effects of TNF-α deletion on iNKT cell development, activation, and maturation in the steady-state and chronic alcohol-consuming mice.

Cytokines play critical roles in regulating iNKT cell development, activation, and maturation. TNF-α co-occurs with iNKT cells in steady-state and many disease conditions. How TNF-α affects iNKT cell function has not been thoroughly investigated. It was found that chronic alcohol consumption enhanced iNKT cell activation and maturation. The underlying mechanism is not known. Herein, a TNF-α KO mouse model was used to address these issues. It was found that the depletion of TNF-α mitigated alcohol consumption-enhanced iNKT cell activation and maturation. In steady-state, depletion of TNF-α did not affect the frequency of iNKT cells in the thymus and spleen but decreased iNKT cells in the liver and increased liver iNKT cell apoptosis. The portion of stage-2 immature iNKT cells increased, stage-3 mature iNKT cells decreased in the thymus of TNF-α KO mice, suggesting that depletion of TNF-α impairs iNKT cell development and maturation. The percentage of CD69+ iNKT cells was significantly lower in the thymus, spleen, and liver of TNF-α KO mice compared to their wild-type littermates, suggesting that depletion of TNF-α inhibits iNKT cell activation. Moreover, the percentage of splenic IL-4- and IFN-γ-producing iNKT cells was significantly lower in TNF-α KO mice than in their wild-type littermates. The depletion of TNF-α increased PLZF+ iNKT cells in the thymus and down-regulated the expression of CD122 on iNKT cells. Collectively, these results support that TNF-α plays a vital role in the regulation of iNKT cell development, activation, and maturation, and alcohol consumption enhances iNKT cell activation and maturation through TNF-α. ©2021 Society for Leukocyte Biology.