CD5 dynamically calibrates basal NF-κB signaling in T cells during thymic development and peripheral activation

Proc Natl Acad Sci U S A. 2020 Jun 23;117(25):14342-14353. doi: 10.1073/pnas.1922525117. Epub 2020 Jun 8.


Immature T cells undergo a process of positive selection in the thymus when their new T cell receptor (TCR) engages and signals in response to self-peptides. As the T cell matures, a slew of negative regulatory molecules, including the inhibitory surface glycoprotein CD5, are up-regulated in proportion to the strength of the self-peptide signal. Together these regulators dampen TCR-proximal signaling and help avoid any subsequent peripheral activation of T cells by self-peptides. Paradoxically, antigen-specific T cells initially expressing more CD5 (CD5hi) have been found to better persist as effector/memory cells after a peripheral challenge. The molecular mechanisms underlying such a duality in CD5 function is not clear. We found that CD5 alters the basal activity of the NF-κB signaling in resting peripheral T cells. When CD5 was conditionally ablated, T cells were unable to maintain higher expression of the cytoplasmic NF-κB inhibitor IκBα. Consistent with this, resting CD5hi T cells expressed more of the NF-κB p65 protein than CD5lo cells, without significant increases in transcript levels, in the absence of TCR signals. This posttranslationally stabilized cellular NF-κB depot potentially confers a survival advantage to CD5hi T cells over CD5lo ones. Taken together, these data suggest a two-step model whereby the strength of self-peptide-induced TCR signal lead to the up-regulation of CD5, which subsequently maintains a proportional reserve of NF-κB in peripheral T cells poised for responding to agonistic antigen-driven T cell activation.

Keywords: CD5; T cell activation; TCR signaling.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antigen Presentation / immunology
  • CD5 Antigens / genetics
  • CD5 Antigens / metabolism*
  • Cell Line, Tumor
  • Cell Separation
  • Cell Survival / immunology
  • Female
  • Flow Cytometry
  • Gene Expression Regulation, Developmental / immunology*
  • Lipopolysaccharides / immunology
  • Lymphocyte Activation
  • Mice
  • Mice, Knockout
  • Models, Animal
  • NF-KappaB Inhibitor alpha / metabolism*
  • Primary Cell Culture
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism*
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism
  • Signal Transduction / immunology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / transplantation
  • Thymus Gland / cytology
  • Thymus Gland / growth & development
  • Thymus Gland / immunology
  • Transcription Factor RelA / metabolism
  • Up-Regulation


  • CD5 Antigens
  • Cd5 protein, mouse
  • Lipopolysaccharides
  • Nfkbia protein, mouse
  • Receptors, Antigen, T-Cell, alpha-beta
  • Rela protein, mouse
  • Transcription Factor RelA
  • NF-KappaB Inhibitor alpha
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Ptpn6 protein, mouse