Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is downstream of multiple cytokines including IL-6, IL-10 and IL-21. Loss-of-function mutations in STAT3 lead to the primary immunodeficiency autosomal-dominant hyper IgE syndrome (AD-HIES). This is a disease characterized by susceptibility to infection by pathogens such as C. albicans and S. aureus due to defective Th17 responses, and a failure to generate effective humoral immune responses. The inability to generate an effective humoral immune response stems from the inability of B cells to respond to the cytokines IL-10 and IL-21. This unresponsiveness leads to reduced antigen specific antibodies, less class switching to IgG and significantly lower numbers of memory B cells. Interestingly, although the number of memory B cells is greatly reduced in AD-HIES patients, they are functionally responsive to the STAT3 signaling cytokines IL-10 and IL-21. Further investigation into STAT3 signaling in healthy human naïve and memory B cells has shown that memory B cells are more sensitive and respond more strongly to IL-21 stimulation.
In this study we have investigated these differences in the molecular sensitivity and requirements of STAT3 signaling in naïve and memory B cells. We have used the techniques ATAC-seq and RNA-seq, to further explore the accessibility of chromatin and the transcriptional profile of primary human naïve and memory B cells. This revealed multiple differences in the accessibility of chromatin between these two subsets and the speed at which genes were induced by IL-21 stimulation. These analyses provide new insight into the molecular changes involved in early naïve and memory B cell activation.