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Author Notes:



Author contributions: W.M.Z.-K., A.W., and B.B.A.-Y. designed research; W.M.Z.-K. and B.B.A.-Y. performed research; W.M.Z.-K., A.W., and B.B.A.-Y. analyzed data; and A.W. and B.B.A.-Y. wrote the paper.

We thank A. Roque for animal husbandry and Z. Wang for cell sorting at University of California, San Francisco; the Pediatrics/Winship Flow Cytometry Core and the Emory University School of Medicine Flow Cytometry Core for cell sorting; C. Hartigan for technical assistance with phospho-ERK assays; and J. Zikherman, W.-L. Lo, H. Wang, and K. Cashman for providing constructive feedback.

The authors declare no conflict of interest.


Research Funding:

Funding for this project was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases K01AR06548 (to B.B.A.-Y.) and National Institute of Allergy and Infectious Diseases 2P01AI091580 (to A.W.).


  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • Nur77
  • CD5
  • T cell activation
  • basal TCR signaling
  • T cell anergy

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


Journal Title:

Proceedings of the National Academy of Sciences


Volume 116, Number 30


, Pages 15160-15169

Type of Work:

Article | Final Publisher PDF


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.

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© 2019 National Academy of Sciences. All rights reserved.

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