Zbtb10 transcription factor is crucial for murine cDC1 activation and cytokine secretion

Abstract

Dendritic cell (DC) activation and cytokine production is tightly regulated. In this study, we found that Zbtb10 expression is activation dependent and it is essential for the immunogenic function of cDC1. Zbtb10 knockdown (KD) significantly reduced the expression of co-stimulatory genes CD80 and CD86 along with cytokines including IL-12, IL-6, and IL-10, in activated cDC1 Mutu-DC line. Consequently, the clonal expansion of CD44⁺ effector T cells in co-cultured CD4⁺ T cells was drastically reduced owing to significantly reduced IL-2. At the same time, these CD44⁺ effector T cells were unable to differentiate toward Tbet⁺ IFNγ⁺ Th1 subtype. Instead, an increased frequency of Th2 cells expressing GATA3⁺ and IL-13⁺ was observed. Interestingly, in Zbtb10 KD condition the co-cultured T cells depicted increased expression of PD1 and LAG3, the T-cell anergic markers. Moreover, the global transcriptome analysis identified that Zbtb10 is pertinent for DC activation and its depletion in cDC1 completely shuts down their immune responses. Mechanistic analysis revealed that Zbtb10 KD enhanced the expression of NKRF (NF-κB repressing factor) leading to drastic suppression of NF-κB related genes. Zbtb10 KD abrogated p65 and RelB nuclear translocation, thereby controlling the activation and maturation of cDC1 and the ensuing adaptive T cell responses.

Keywords: NFkB; Th1 cells; Th2 cells; Zbtb10; cDC1.