Naïve T Cell Homeostasis Regulated by Stress Responses and TCR Signaling

Abstract

The survival of naïve T cells is believed to require signals from TCR-pMHC interactions and cytokines such as IL-7. In contrast, signals that negatively impact naïve T cell survival are less understood. We conducted a forward genetic screening of mice and found a mutant mouse line with reduced number of naïve T cells (T-Red mice). T-Red mice have a point mutation in the Kdelr1 gene, and their naïve T cells show enhanced integrated stress response (ISR), which eventually induces their apoptosis. Therefore, naïve T cells require a KDEL receptor-mediated mechanism that efficiently relieves cellular stress for their survival in vivo. Interestingly, naïve T cells expressing TCR with higher affinity/avidity to self-antigens survive in T-Red mice, suggesting the possible link between TCR-mediated survival and ISR-induced apoptosis. In this article, we discuss the regulation of naïve T cell homeostasis, keeping special attention on the ISR and TCR signal.

Keywords: T cell homeostasis; TCR signaling; mutagenesis; naive T cells; stress response.

Figure 1

The Kdelr1–PP1 axis is required for naïve T cell survival. In WT naïve T cells, PP1 associated with Kdelr1 exhibits optimal phosphatase activity to prevent unwanted persistence of ISR. In T-Red naïve T cells, however, Kdelr1 dysfunction results in reduced PP1 activity, leading to prolonged ISR and apoptosis. Endogenous factors that cause ISR in vivo remain unidentified.

Figure 2

Strong TCR-mediated signals alleviate ISR in T-Red naïve T cells. T-Red naïve T cells expressing TCR with relatively high self-affinity are resistant to enhanced ISR caused by Kdelr1 dysfunction. Further studies are required to reveal the specific TCR signaling that counteracts ISR.