Accumulation of TCR signaling from self-antigens in naive CD8 T cells mitigates early responsiveness.

• Authors: Joel Eggert, Emory University; Wendy Zinzow-Kramer, Emory University; Yuesong Hu, Emory University; Yuan-Li Tsai, University of California, San Francisco; Arthur Weiss; Khalid Salaita, Emory University; Christopher Scharer, Emory University; Byron Au-Yeung, Emory University
• Journal Title: bioRxiv
• Publisher: bioRxiv | 2023-01-28
• Type of Work: Article | Preprint: Prior to Peer Review
• Publisher DOI: http://doi.org/10.1101/2023.01.27.525946
• Subjects: Health Sciences, Medicine and Surgery; Biology, Microbiology; Health Sciences, Immunology
• Keywords: TCR signaling; self-antigens

Abstract

The cumulative effects of T cell receptor (TCR) signal transduction over extended periods of time influences T cell biology, such as the positive selection of immature thymocytes or the proliferative responses of naive T cells. Naive T cells experience recurrent TCR signaling in response to self-antigens in the steady state. However, how these signals influence the responsiveness of naive CD8 + T cells to subsequent agonist TCR stimulation remains incompletely understood. We investigated how naive CD8 + T cells that experienced relatively low or high levels of TCR signaling in response to self-antigens respond to stimulation with foreign antigens. A transcriptional reporter of Nr4a1 (Nur77-GFP) revealed substantial heterogeneity of the amount of TCR signaling naive CD8 + T cells accumulate in the steady state. Nur77-GFP HI cells exhibited diminished T cell activation and secretion of IFNγ and IL-2 relative to Nur77-GFP LO cells in response to agonist TCR stimulation. Differential gene expression analyses revealed upregulation of genes associated with acutely stimulated T cells in Nur77-GFP HI cells but also increased expression of negative regulators such as the phosphatase Sts1. Responsiveness of Nur77-GFP HI cells to TCR stimulation was partially restored at the level of IFNγ secretion by deficiency of Sts1 or the ubiquitin ligase Cbl-b. Our data suggest that extensive accumulation of TCR signaling during steady state conditions induces a recalibration of the responsiveness of naive CD8 + T cells through gene expression changes and negative regulation, at least in part, dependent on Sts1 and Cbl-b. This cell-intrinsic negative feedback loop may allow the immune system to limit the autoreactive potential of highly self-reactive naive CD8 + T cells.