Circulating subset of iNKT cells mediates antitumor and antiviral immunity

 GUANGWEI CUI HTTPS://ORCID.ORG/0000-0002-3276-1926 AKIHIRO SHIMBAJIANSHI JIN HTTPS://ORCID.ORG/0000-0003-4697-8760TAISAKU OGAWAYUKIKO MURAMOTO HTTPS://ORCID.ORG/0000-0002-8706-3113HITOSHI MIYACHI HTTPS://ORCID.ORG/0000-0002-4855-3857SHINYA ABE HTTPS://ORCID.ORG/0000-0002-2707-1947TAKUMA ASAHI HTTPS://ORCID.ORG/0000-0001-6372-7563SHIZUE TANI-ICHI HTTPS://ORCID.ORG/0000-0003-2388-776X[...]KOICHI IKUTA HTTPS://ORCID.ORG/0000-0003-1319-1021 

DOI: 10.1126/sciimmunol.abj8760

Circulating iNKT cells protect

Invariant natural killer T (iNKT) cells are tissue-resident, innate-like T cells that recognize lipid antigens and are involved in immune regulation. The heterogeneity and development of iNKT cell populations has not been well defined; thus, Cui et al. used various mouse models, transcriptomics, flow cytometry, and histology to better understand iNKT subpopulations. The authors uncovered a circulating population of iNKT cells that expressed CD244 and CXCR6 and were distinct from conventional iNKT cells in mice and humans. This iNKT subset depended on IL-15+ medullary thymic epithelial cells for development and maturation. The circulating iNKT cells were highly cytotoxic and protected mice from melanoma metastasis and influenza infection. Thus, the authors uncovered a population of circulating iNKT cells that were highly cytotoxic and protective against various insults.

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.

https://www.science.org/doi/10.1126/sciimmunol.abj8760