biostudies-literatureKamii YThe Ministry of Education, Culture, Sports, Science and TechnologyNIAID NIH HHSThe Ministry of Education, Culture, Sports, Sciences and TechnologyThe Ministry of Education, Culture, Sports, Science and Technology (Japan)The Ministry of Education, Culture, Sports, Sciences and Technology (Japan)e2313964121https://www.ebi.ac.uk/biostudies/studies/S-EPMC10907256biostudies-literatureUnknown121(9)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 (NKT_FH) cells are specialized to help B cells. However, the mechanisms of NKT_FH cell differentiation remain to be elucidated. In this report, we studied the mechanism of NKT_FH 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 NKT_FH cell differentiation in the spleen by producing interleukin-27 (IL-27) in the early phase after vaccination. The neutralization of IL-27 impaired NKT_FH cell differentiation, which resulted in compromised antibody production and diminished protection against <i>Streptococcus pneumoniae</i> 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 NKT_FH 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.Proceedings of the National Academy of Sciences of the United States of AmericaIL-27 regulates the differentiation of follicular helper NKT cells via metabolic adaptation of mitochondria.PMC10907256#19H03705 #22H03123R37 AI071922#19K16704 #21K07085Ohteki TKawakami KSaito MChiba AKuwano KIkegami TYoshida KAraya JKinjo YKronenberg MKanno TEndo YHayashizaki KAkeda YKamii YOishi KKubo MfalseIL-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 (NKT_FH) cells are specialized to help B cells. However, the mechanisms of NKT_FH cell differentiation remain to be elucidated. In this report, we studied the mechanism of NKT_FH 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 NKT_FH cell differentiation in the spleen by producing interleukin-27 (IL-27) in the early phase after vaccination. The neutralization of IL-27 impaired NKT_FH cell differentiation, which resulted in compromised antibody production and diminished protection against <i>Streptococcus pneumoniae</i> 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 NKT_FH 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.2024-01-01T00:00:00Z2024 Feb2025-04-19T17:49:29.91Z2025-04-19T17:49:29.91ZS-EPMC109072563839424210.1073/pnas.2313964121