Kiyotsugu Yoshida

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.

Dual‐specificity tyrosine‐regulated kinase 2 (DYRK2) is a protein kinase that phosphorylates p53‐Ser46 and induces apoptosis in response to DNA damage. However, the relationship between DYRK2 expression and chemosensitivity after DNA damage in colorectal cancer has not been well investigated. The aim of the present study was to examine whether DYRK2 could be a novel marker for predicting chemosensitivity after 5‐fluorouracil‐ and oxaliplatin‐induced DNA damage in colorectal cancer. Here we showed that DYRK2 knockout decreased the chemosensitivity to 5‐fluorouracil and oxaliplatin in p53 wild‐type colorectal cancer cells, whereas the chemosensitivity remained unchanged in p53‐deficient/mutated colorectal cancer cells. In addition, no significant differences in chemosensitivity to 5‐fluorouracil and oxaliplatin between scramble and siDYRK2 p53(−/−) colorectal cancer cells were observed. Conversely, the combination of adenovirus‐mediated overexpression of DYRK2 with 5‐fluorouracil or oxaliplatin enhanced apoptosis and chemosensitivity through p53‐Ser46 phosphorylation in p53 wild‐type colorectal cancer cells. Furthermore, DYRK2 knockout decreased chemosensitivity to 5‐fluorouracil and oxaliplatin in p53 wild‐type xenograft mouse models. Taken together, these findings demonstrated that DYRK2 expression was associated with chemosensitivity to 5‐fluorouracil and oxaliplatin in p53 wild‐type colorectal cancer, suggesting the importance of evaluating the p53 status and DYRK2 expression as a novel marker in therapeutic strategies for colorectal cancer.