The E3 ubiquitin ligase Itch is required for the differentiation of follicular helper T cells

The molecular mechanisms that regulate the induction of follicular helper T cells (T FH cells) remain unclear. Liu and colleagues show that the E3 ubiquitin ligase Itch regulates T FH cell differentiation through ubiquitination and degradation of the transcription factor Foxo1. Follicular helper T cells (T FH cells) are responsible for effective B cell–mediated immunity, and Bcl-6 is a central factor for the differentiation of T FH cells. However, the molecular mechanisms that regulate the induction of T FH cells remain unclear. Here we found that the E3 ubiquitin ligase Itch was essential for the differentiation of T FH cells, germinal center responses and immunoglobulin G (IgG) responses to acute viral infection. Itch acted intrinsically in CD4 + T cells at early stages of T FH cell development. Itch seemed to act upstream of Bcl-6 expression, as Bcl-6 expression was substantially impaired in Itch −/− cells, and the differentiation of Itch −/− T cells into T FH cells was restored by enforced expression of Bcl-6. Itch associated with the transcription factor Foxo1 and promoted its ubiquitination and degradation. The defective T FH differentiation of Itch −/− T cells was rectified by deletion of Foxo1 . Thus, our results indicate that Itch acts as an essential positive regulator in the differentiation of T FH cells.