The production of IFN-γ
by iNKT cells can quickly transactivate tissue-resident NK cells, γδ T cells and other lymphocytes, like B cells. Invariant NKT cells can also provide help for B cells, by inducing their maturation and increasing their antibody-producing functions. Furthermore, interactions of iNKT cells with antigen-presenting cells are bi-directional; when dendritic cells present lipid antigens through CD1d to iNKT cells, Akt inhibitor this induces IFN-γ production by iNKT cells and also induces further IL-12 production by dendritic cells through CD40–CD40 ligand interactions. This interaction is important for dendritic cell maturation, and as dendritic cell maturation is important for the initiation of the adaptive immune response, this is another example of how iNKT cells can act as a bridge between the innate and adaptive systems.
The potent regulatory potential of iNKT cells is evident in many diseases. Invariant NKT cell defects have been seen in human autoimmune diseases, including type I diabetes, systemic lupus erythematosus and multiple sclerosis, and also in cancer.[30, 35, 36] In humans, cancer and infections MK-2206 in vitro are also associated with defects in iNKT cells. As iNKT cells have anti-tumour activity, either through their cytotoxic potential against CD1d on tumour cells, or through their activation CYTH4 of NK cells, they have been shown to be protective against many types of cancer. Many clinical trials in cancer have been designed to target the immunoregulatory potential of iNKT cells by increasing the number of NKT
cells or stimulating their production of cytokines so that they might kick-start an immune response against the tumour. More direct evidence of iNKT regulation comes from mice that are completely deficient in iNKT cells or from studies that activate iNKT cells by injecting αGalCer in murine models of disease. Mice lacking iNKT cells (Ja18−/− and CD1d−/−) are generally healthy but are more prone to spontaneously develop autoimmunity and cancer, as well as often having impaired responses to pathogens. Hence, through their regulatory actions on many different immune cells, iNKT cell functions are broad in healthy and disease settings. Invariant NKT cells develop in the thymus from the same precursors as MHC-restricted T cells. They are derived from double-positive thymocytes through stochastic expression of their invariant TCR, followed by positive selection on CD1d expressed by other thhymic double-positive cells, rather than CD1d on epithelial cells.[29, 37] The iNKT cells then exit the thymus and primarily home to tissues where they complete their maturation.