Costimulation molecules differentially regulate the ERK-Zfp831 axis to shape T follicular helper cell differentiation

T follicular helper (Tfh) cells play essential roles in regulating humoral immunity, especially germinal center reactions. However, how CD4(+) T cells integrate the antigenic and costimulatory signals in Tfh cell development is still poorly understood. Here, we found that phorbol 12-myristate 13-acetate (PMA) + ionomycin (P+I) stimulation, together with interleukin-6 (1L-6), potently induce Tfh cell-like transcriptomic programs in vitro. The ERK kinase pathway was attenuated under P+I stimulation; ERK2 inhibition enhanced Tfh cell development in vitro and in vivo. We observed that inducible T cell costimulator (ICOS), but not CD28, lacked the ability to activate ERK, which was important in sustaining Tfh cell development. The transcription factor Zfp831, whose expression was repressed by ERK, promoted Tfh cell differentiation by directly upregulating the expression of the transcription factors Bcl6 and Tcf7. We have hence identified an ERK-Zfp831 axis, regulated by costimulation signaling, in critical regulation of Tfh cell development.

Automated summary

The study revealed that PMA + ionomycin stimulation combined with IL-6 can induce Tfh cell-like transcriptomic programs in vitro, and inhibition of ERK2 can enhance Tfh cell development. Additionally, ICOS lacks the ability to activate ERK, while Zfp831 promotes Tfh cell differentiation by upregulating the expression of Bcl6 and Tcf7.