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 (IL-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. [Display omitted] • PMA + ionomycin promote Tfh cell generation in vitro • ERK kinase pathway negatively regulates Tfh cell differentiation program • CD28 and ICOS signaling differentially regulate ERK during Tfh cell differentiation • Repressed by ERK, Zfp831 is a transcription factor that promotes Tfh cell development Tfh cell essentially regulates humoral immunity, but its differentiation process is not fully understood. Wan et al. reveal that ICOS and CD28 differentially regulate the ERK kinase pathway and ERK is Tfh-repressive. Repressed by ERK, the transcriptional factor Zfp831 promotes T follicular helper cell differentiation. [ABSTRACT FROM AUTHOR]