ELF4 bridges transcriptional and translational outputs to regulate inflammatory T Cells 3617

Abstract Description The transcription factor ELF4 generally acts as a brake on the immune system, as patients with Deficiency in ELF4 X-linked (DEX) exhibit symptoms of hyperinflammation. While it has been demonstrated by our lab that global loss of ELF4 results in hyper-cytokine release in macrophages and restrains Th17 differentiation in mice, the breadth and mechanisms of CD4+ T cell regulation by ELF4 remain enigmatic. Here, we show that loss of T cell-intrinsic ELF4 leads to enhanced interferon gamma (IFNγ) production at the protein, but not transcript, level. In line with this, absence of T cell-intrinsic ELF4 leads to decreased expression of several targets of the integrated stress response, demonstrated to be crucial in restraining cytokine production via inhibition of cap-dependent translation during initial activation of naïve T cells. Using stable isotope labeling with amino acids in cell culture (SILAC), we demonstrate ELF4 specifically limits the translation of IFNγ, while upregulating the production of factors known to inhibit cap-dependent translation, Eif4ebp1 and Eif4ebp2. T cell-intrinsic ELF4 deficiency in the context of infection with Lymphocytic Choriomeningitis virus resulted in enhanced IFNγ production by CD4+ T cells during initial infection as well as enhanced multi-cytokine production of memory CD4+ T cells. Thus, we elucidate an essential mechanism for restraining CD4+ T cell inflammatory potential dependent on regulation of the integrated stress response by ELF4. Funding Sources Mathers Foundation, Rainin Foundation, NIAID/NIH Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)