A circulating subset of iNKT cells mediates antitumor and antiviral immunity

Abstract

Invariant natural killer T (iNKT) cells are a group of innate-like T lymphocytes that recognize lipid antigens. They are supposed to be tissue resident and important for systemic and local immune regulation. To investigate the heterogeneity of iNKT cells, we recharacterized iNKT cells in the thymus and peripheral tissues. iNKT cells in the thymus were divided into three subpopulations by the expression of the natural killer cell receptor CD244 and the chemokine receptor CXCR6 and designated as C0 (CD244 − CXCR6 − ), C1 (CD244 − CXCR6 + ), or C2 (CD244 + CXCR6 + ) iNKT cells. The development and maturation of C2 iNKT cells from C0 iNKT cells strictly depended on IL-15 produced by thymic epithelial cells. C2 iNKT cells expressed high levels of IFN-γ and granzymes and exhibited more NK cell–like features, whereas C1 iNKT cells showed more T cell–like characteristics. C2 iNKT cells were influenced by the microbiome and aging and suppressed the expression of the autoimmune regulator AIRE in the thymus. In peripheral tissues, C2 iNKT cells were circulating that were distinct from conventional tissue-resident C1 iNKT cells. Functionally, C2 iNKT cells protected mice from the tumor metastasis of melanoma cells by enhancing antitumor immunity and promoted antiviral immune responses against influenza virus infection. Furthermore, we identified human CD244 + CXCR6 + iNKT cells with high cytotoxic properties as a counterpart of mouse C2 iNKT cells. Thus, this study reveals a circulating subset of iNKT cells with NK cell–like properties distinct from conventional tissue-resident iNKT cells.

SOX chemotherapy with anti-PD-1 and iNKT cell immunotherapies for stage IV gastric adenocarcinoma with liver metastases: A case report

“…A recent study showed that a circulating subset of iNKT cells with NK cell-like properties in the peripheral blood in human exhibit enhancing antitumor immunity and antiviral immune responses ( 19 ). Accumulating evidence in numerous human cancers supports a strong positive correlation between overall survival and the frequency and function of iNKT cells in the tumor or in circulation ( 20 – 24 ).…”

Towards a better understanding of human iNKT cell subpopulations for improved clinical outcomes

“…There have been several clinical trial efforts attempting to use the strong iNKT agonist lipid αGalCer to activate this subset of T cells or through using adoptive iNKT cell immunotherapy ( Table 1 ). However, plenty of evidence suggests the existence of a more diverse human iNKT repertoire, leading to investigations of specific subsets which has the potential to improve future iNKT-targeted cell therapies ( 38 ).…”

“…A further potential strategy proposed here is the selection and utilisation of specific human iNKT cell subsets to achieve improved outcomes in iNKT-based cancer immunotherapy. This proposal is based on studies revealing that iNKT cells exist as subpopulations with a previously unrecognised diversity in function ( 19 , 25 , 38 , 97 ). iNKT cells are not a single, uniform class of T cells as they exhibit heterogeneity in both phenotype and function.…”

“…Human CD4 + iNKT cells are broadly associated with Th0-type immune responses and are the exclusive producers of IL-4 and IL-13 upon primary stimulation; whereas, DN iNKT cells have a strict Th1 profile and prominently express several NK lineage receptors ( 107 ). Additionally, it has been shown that CD244 + CXCR6 + iNKT cells, which are present in mice and humans, have enhanced cytotoxic properties producing more IFN-γ compared to CD244 - CXCR6 - iNKT cells ( 38 ). Intriguingly, this CD244 + CXCR6 + iNKT cell subset is CD4 - , potentially explaining the enhanced cytotoxic function of the CD4 - iNKT cell subset ( 38 ).…”

“…Additionally, it has been shown that CD244 + CXCR6 + iNKT cells, which are present in mice and humans, have enhanced cytotoxic properties producing more IFN-γ compared to CD244 - CXCR6 - iNKT cells ( 38 ). Intriguingly, this CD244 + CXCR6 + iNKT cell subset is CD4 - , potentially explaining the enhanced cytotoxic function of the CD4 - iNKT cell subset ( 38 ).…”