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 (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 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 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.