Adaptation by naive CD4(+) T cells to self-antigen-dependent TCR signaling induces functional heterogeneity and tolerance

• Authors: Wendy Zinzow-Kramer, Emory University; Arthur Weiss, University of California San Francisco; Byron Au-Yeung, Emory University
• Journal Title: Proceedings of the National Academy of Sciences
• Volume: Volume 116, Number 30
• Publisher: National Academy of Sciences | 2019-07-23, Pages 15160-15169
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1073/pnas.1904096116
• Subjects: Health Sciences, Immunology; Biology, Cell
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; Nur77; CD5; T cell activation; basal TCR signaling; T cell anergy; POSITIVE SELECTION; CATALYTIC-ACTIVITY; SENSITIVITY; RECOGNITION; HOMEOSTASIS; REPERTOIRE; MECHANISMS; THRESHOLD; RESPONSES; STRENGTH

Abstract

Naïve CD4+ T cells experience weak T cell receptor (TCR) signals induced by self-peptides presented by MHC II. To investigate how these “basal” TCR signals influence responses to agonist TCR ligand stimulation, we analyzed naïve CD4+ cells expressing varying amounts of CD5, Ly6C, and Nur77-GFP, markers that reflect the strength of basal TCR signaling. Phenotypic analyses indicate that the broadest range of basal TCR signal strength can be visualized by a combination of Nur77-GFP and Ly6C. A range of basal TCR signaling is detectable even in populations that express identical TCRs. Whereas moderate basal TCR signal strength correlates with higher IL-2 secretion at early time points following TCR stimulation, weak basal TCR signaling correlated with higher IL-2 secretion at later time points. We identify a population of Nur77-GFPHI Ly6C− cells that could not be reliably marked by either of CD5, Ly6C, or Nur77-GFP alone. These cells experience the strongest basal TCR signaling, consistently produce less IL-2, and express PD-1 and markers associated with anergy, such as Grail and Cbl-b. We propose that adaptation to the strength of basal TCR signaling drives the phenotypic and functional heterogeneity of naïve CD4+ cells.