Natural Killer T Cell Diversity and Immunotherapy

Abstract

Invariant natural killer T cells (iNKTs), a type of unconventional T cells, share features with NK cells and have an invariant T cell receptor (TCR), which recognizes lipid antigens loaded on CD1d molecules, a major histocompatibility complex class I (MHC-I)-like protein. This interaction produces the secretion of a wide array of cytokines by these cells, including interferon gamma (IFN-γ) and interleukin 4 (IL-4), allowing iNKTs to link innate with adaptive responses. Interestingly, molecules that bind CD1d have been identified that enable the modulation of these cells, highlighting their potential pro-inflammatory and immunosuppressive capacities, as required in different clinical settings. In this review, we summarize key features of iNKTs and current understandings of modulatory α-galactosylceramide (α-GalCer) variants, a model iNKT cell activator that can shift the outcome of adaptive immune responses. Furthermore, we discuss advances in the development of strategies that modulate these cells to target pathologies that are considerable healthcare burdens. Finally, we recapitulate findings supporting a role for iNKTs in infectious diseases and tumor immunotherapy.

Rationally Designed Highly Potent NKT Cell Agonists with Different Cytokine Selectivity through Hydrogen-Bond Interaction

“…2,3 Among diversified immune cell populations, natural killer T (NKT) cells have potent immunoregulatory activities that bridge the innate and adaptive immunity, serving as the "Swiss-Army knife" in the immune system. 3,4 Activation of NKT cells prompts the release of various cytokines, including Th1 (e.g., IFN-γ) and Th2 cytokines (e.g., IL-4). 2−4 In recent years, NKT cell ligands have attracted considerable attention for their utilization in immunotherapy and vaccine adjuvants, especially those that can provoke potent Th1 responses for anticancer and antiviral outcomes.…”

“…Cancer immunotherapy has emerged as a revolutionizing field to fight cancer by stimulating the innate or adaptive immune systems . Harnessing Th1 immune responses is crucial in cancer immunotherapy to achieve durable and effective cellular responses to eradicate tumor cells. , Among diversified immune cell populations, natural killer T (NKT) cells have potent immunoregulatory activities that bridge the innate and adaptive immunity, serving as the “Swiss-Army knife” in the immune system. , Activation of NKT cells prompts the release of various cytokines, including Th1 (e.g., IFN-γ) and Th2 cytokines (e.g., IL-4). − In recent years, NKT cell ligands have attracted considerable attention for their utilization in immunotherapy and vaccine adjuvants, especially those that can provoke potent Th1 responses for anticancer and antiviral outcomes. ,,− Nevertheless, stimulants that elicit a mixed Th1/Th2 response are still needed for applications that require a balanced activation of both humoral and cellular responses. , …”

“…1 Harnessing Th1 immune responses is crucial in cancer immunotherapy to achieve durable and effective cellular responses to eradicate tumor cells. 2,3 Among diversified immune cell populations, natural killer T (NKT) cells have potent immunoregulatory activities that bridge the innate and adaptive immunity, serving as the "Swiss-Army knife" in the immune system. 3,4 Activation of NKT cells prompts the release of various cytokines, including Th1 (e.g., IFN-γ) and Th2 cytokines (e.g., IL-4).…”