Single-cell transcriptomics reveals 14-3-3ζ as a novel regulator of differentiation and tissue distribution of immune cells 4717

Abstract Description Signal transductions are fundamental for the differentiation and activation of immune cells. Our laboratory studies 14-3-3z, a ubiquitously expressed cellular adaptor protein, binds signaling intermediates and regulates functional outcomes. We recently showed that it functions as an autoantigen that inhibits inflammatory arthritis in animals by suppressing the production of IL-1b. It suppresses inflammatory cytokine synthesis, RANKL signaling, and osteoclast differentiation, thus protecting against inflammatory bone loss when subjected to external stimuli. To evaluate the physiological relevance of 14-3-3z function as an immune regulator, we compared immune cell distribution in the lymphoid tissues and peripheral circulation of wild-type and 14-3-3zKO animals using single-cell transcriptomics approach. Our results show that the lack of 14-3-3z caused significant changes in the distribution of lymphocytes (T, B, and NK cells) and myeloid cells (monocytes, macrophages, and DC) in both lymphoid tissues and peripheral circulation without external stimuli. The prominent changes included reduced regulatory but increased inflammatory immune cells. Importantly, our results indicate that 14-3-3z regulates several transcription factors required to differentiate lymphocytes and monocytes. Our presentation will reveal how 14-3-3z regulates different transcription factors in various cell types and regulates their activation in favor of immune suppression. Funding Sources Supported by NIH/NIAID IA-184880, URFO UToledo, Medical Research Society, and Private donor Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)