Effects of TNFα signaling on iNKT cell development, activation and maturation

Abstract

Abstract iNKT cells are CD1d-restricted T cells that recognize lipid antigens. Upon activation these cells rapidly produce large amount and a broad spectrum of cytokines. They are important immunoregulatory cells involved in autoimmune disease, liver injury and antitumor immunity. The mechanisms regarding iNKT cell development, activation and maturation have been studied extensively. It is well known that many cytokines and transcription factors are involved in these processes. TNFα, an inflammatory cytokine that can be produced by iNKT cells, co-occurs with iNKT cells in steady state and many disease conditions. How TNFα affects iNKT cell development, activation and maturation is not known. Herein we used a TNFα KO mouse model to address this issue. We found that depletion of TNFα did not affect the frequency of iNKT cells in thymus and spleen, but decreased iNKT cells in liver, and increased iNKT cell apoptosis in liver. The portion of stage-2 (NK1.1loCD44hi) iNKT cells increased, stage-3 (NK1.1hiCD44hi) iNKT cells decreased in the thymus of TNFα KO mice, suggesting that depletion of TNFα impairs iNKT cell development and maturation. The percentage of CD69+ iNKT cells was significantly lower in the thymus, spleen and liver of TNFα KO mice compared to their wild-type littermates, suggesting that depletion of TNFα inhibits iNKT cell activation. Moreover, upon activation, the percentage of splenic IL-4- and IFN-g-producing iNKT cells was significantly lower in TNFα KO mice than in their wild-type littermates. Depletion of TNFα increased PLZF+ iNKT cells in thymus and downregulated the expression of CD122 on iNKT cells. Taken together, TNFα signaling plays important roles in regulation of iNKT cell development, activation and maturation.