196 Immune pathology caused by intrinsic loss of control in CD4 T cells

Background Naive T cells constantly see self, need to avoid spontaneous immunity, yet be primed to react to foreign antigens when an infection occurs. Both CD4 +and CD8+primary T cells exhibit tonic signaling (Myers et al., 2017b) and continuous interactions of the TCR with self-p/MHC generate tonic signals (Stefanova et al., 2002). T cells lacking the central adapter molecule LAT cause a spontaneous lymphoproliferative T helper 2 (TH2) cell syndrome in mice. Thus, LAT constitutes an unexplained maintenance cue. Our studies of a mouse model with a single nucleotide variant in Rasgrp1, Rasgrp1Anaef, and autoimmune features suggested that basal mTOR signals impact the resting state of T cells in vivo (Daley et al., 2013). We set out to investigate if tonic signals in primary T cells establish a primed yet controlled state. Methods A sophisticated mouse model allowing for inducible deletion of the adapter LAT in T cells was coupled to quantitative biochemical analyses of primary T cells, gene expression analyses, and functional T cell assays, Through our Rasgrp1Anaef mouse model, quantitative biochemical analyses of primary T cells, and genome-wide ribosome profiling, we established that tonic mTORC1 signals shape the baseline translational landscape in resting T cells in vivo. Results In 2017, we described how tonic signals prevent aberrant basal activity of naive T cells; Tonic signals through LAT (Linker for activation of T cells) and the transcriptional regulator HDAC7 maintain mRNA expression of a cluster of target genes that are negative regulators of spurious T cell proliferation and Th2 differentiation (Myers et al., 2017a). We recently discovered robust and selective mTORC1 kinase signals in resting, naive CD4 +T cells. We find that RasGRP1 is necessary and sufficient to generate tonic mTORC1 signals. These tonic mTORC1 signals govern a baseline translational program and impact the capacity of CD4 +T cells to take on effector functions (Myers et al., in revision). Aberrantly increased tonic mTORC1 signals in a Rasgrp1Anaef mouse model (Daley et al., 2013) drive immune pathology, alter the ribosome profiles of resting T cells, and enhance differentiation to the Tph, Tfh, and Th2 fates. Conclusions Our fundamental studies on tonic signals demonstrate a dynamic balance in naive T cells with an inhibitory arm regulated through tonic gene expression and a stimulatory arm by shaping a basal translational landscape that includes a mTOR signature. Dysregulation of mTORC1 signaling has been implicated in autoimmune diseases and T cells from systemic lupus erythematosus (SLE) patients exhibit mTORC1 activation (Perl, 2016). Single nucleotide- and splice- variants of Rasgrp1 have been implicated in SLE (Yasuda et al., 2007), and Type 1 Diabetes and Graves disease (Plagnol et al., 2011; Qu et al., 2009). The mTORC1 inhibitor rapamycin can block T cell activation in SLE patients and has therapeutic efficacy in SLE (Perl, 2016). We believe that our fundamental studies provide a novel platform for investigating tonic signal activity in T cells from autoimmune patients and will discuss latest progress. Funding Source(s): NSF-GRFP (1650113 to DRM) and the NIH-NIAID (R01-AI104789 and P01-AI091580 to JPR). Are altered tonic signals in T cells a common consequence of single nucleotide variants (SNVs)?