IL-27 regulates the differentiation of follicular helper NKT cells via metabolic adaptation of mitochondria.

Invariant natural killer T (iNKT) cells are innate-like T lymphocytes that express an invariant T cell receptor α chain and contribute to bridging innate and acquired immunity with rapid production of large amounts of cytokines after stimulation. Among effecter subsets of iNKT cells, follicular helper NKT (NKTFH) cells are specialized to help B cells. However, the mechanisms of NKTFH cell differentiation remain to be elucidated. In this report, we studied the mechanism of NKTFH cell differentiation induced by pneumococcal surface protein A and α-galactosylceramide (P/A) vaccination. We found that Gr-1+ cells helped iNKT cell proliferation and NKTFH cell differentiation in the spleen by producing interleukin-27 (IL-27) in the early phase after vaccination. The neutralization of IL-27 impaired NKTFH cell differentiation, which resulted in compromised antibody production and diminished protection against Streptococcus pneumoniae infection by the P/A vaccine. Our data indicated that Gr-1+ cell-derived IL-27 stimulated mitochondrial metabolism, meeting the energic demand required for iNKT cells to differentiate into NKTFH cells. Interestingly, Gr-1+ cell-derived IL-27 was induced by iNKT cells via interferon-γ production. Collectively, our findings suggest that optimizing the metabolism of iNKT cells was essential for acquiring specific effector functions, and they provide beneficial knowledge on iNKT cell-mediated vaccination-mediated therapeutic strategies.

Citation

Yasuhiro Kamii, Koji Hayashizaki, Toshio Kanno, Akio Chiba, Taku Ikegami, Mitsuru Saito, Yukihiro Akeda, Toshiaki Ohteki, Masato Kubo, Kiyotsugu Yoshida, Kazuyoshi Kawakami, Kazunori Oishi, Jun Araya, Kazuyoshi Kuwano, Mitchell Kronenberg, Yusuke Endo, Yuki Kinjo. IL-27 regulates the differentiation of follicular helper NKT cells via metabolic adaptation of mitochondria. Proceedings of the National Academy of Sciences of the United States of America. 2024 Feb 27;121(9):e2313964121

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PMID: 38394242

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