UCSF

To maintain immunological tolerance and prevent autoimmunity, naïve CD4+ T cells need to be able to discriminate between self and nonself. In addition, naïve T cells need to remain quiescent and prevent spontaneous activation or differentiation, yet they also must be primed to efficiently respond when they do encounter foreign antigen. These features suggest that there must be active mechanisms to regulate the naïve state of CD4+ T cells. We have uncovered that tonic (basal) signaling pathways in peripheral CD4+ T cells dynamically maintain this primed-yet-quiescent state in three manners: transcriptional, translational, and metabolic programs.

We identified a tonic pathway involving the adapter LAT that dynamically controls a transcriptional program in naïve CD4+ T cells. LAT perturbation in T cells leads to a spontaneous Th2-biased lymphoproliferative disease. We found that LAT is critical for tonic regulation of the repressor HDAC7. Tonic signals lead to phosphorylation and cytoplasmic localization of HDAC7. Without basal LAT function, HDAC7 is dephosphorylated and resides in the nucleus, where it represses target genes such as Nur77 and Irf4. Appropriate expression of these genes is important for preventing spontaneous proliferation and differentiation of CD4+ T cells.

Second, we identified a connection between tonic Rasgrp1-mTOR signals and translational programs. CD4+ T cells with a point mutation in the Ras activator Rasgrp1, called Rasgrp1Anaef, exhibit increased basal mTOR signaling and as a result the mice develop autoimmune features. We found that Rasgrp1Anaef CD4+ T cells have an autoreactive TCR repertoire and show increased differentiation to Tfh- and Th2, with concomitant increase in Gata3 protein levels that we hypothesize is caused by increased translation. We are currently investigating what global basal translation programs are regulated by tonic Rasgrp1-mTOR signals in naïve T cells.

Additionally, we are following up on findings that tonic mTOR signals control the metabolic state of naïve T cells and allow for efficient switching of metabolic programs upon T cell activation. Overall, our results provide novel insights into the role of tonic signaling pathways in controlling naïve CD4+ T cells and how point mutations in signaling proteins can disrupt these tonic pathways, leading to perturbed immune function.