Naïve T Cell Homeostasis Regulated by Stress Responses and TCR Signaling

Area of Science:

• Immunology
• Cell Biology
• Genetics

Background:

• Naïve T cell survival is crucial for adaptive immunity, typically requiring T cell receptor (TCR)-pMHC interactions and cytokines like IL-7.
• Mechanisms negatively regulating naïve T cell survival are less understood.
• The integrated stress response (ISR) is a cellular pathway that can lead to apoptosis.

Purpose of the Study:

• To identify genetic factors influencing naïve T cell survival.
• To investigate the role of the KDEL receptor (Kdelr1) in naïve T cell homeostasis.
• To explore the link between TCR signaling, ISR, and T cell apoptosis.

Main Methods:

• Forward genetic screening in mice to identify mutations affecting T cell numbers.
• Characterization of a mutant mouse line (T-Red) with a point mutation in the Kdelr1 gene.
• Analysis of naïve T cell apoptosis, ISR activation, and TCR signaling in T-Red mice.

Main Results:

• T-Red mice exhibit a reduced number of naïve T cells due to enhanced ISR and subsequent apoptosis.
• The Kdelr1 mutation impairs a KDEL receptor-mediated mechanism essential for relieving cellular stress in naïve T cells.
• Naïve T cells with higher affinity/avidity TCRs to self-antigens show improved survival in T-Red mice, indicating a connection between TCR signaling and ISR-induced cell death.

Conclusions:

• KDEL receptor-mediated stress relief is vital for naïve T cell survival in vivo.
• Dysregulation of the ISR pathway, influenced by Kdelr1 function, significantly impacts T cell homeostasis.
• TCR signaling strength may modulate the susceptibility of naïve T cells to ISR-induced apoptosis.