Signaling thresholds govern heterogeneity in IL-7-receptor-mediated responses of naïve CD8(+) T cells

Immunol Cell Biol. 2011 Jul;89(5):581-94. doi: 10.1038/icb.2011.5. Epub 2011 Feb 22.


Variable sensitivity to T-cell-receptor (TCR)- and IL-7-receptor (IL-7R)-mediated homeostatic signals among naïve T cells has thus far been largely attributed to differences in TCR specificity. We show here that even when withdrawn from self-peptide-induced TCR stimulation, CD8(+) T cells exhibit heterogeneous responses to interleukin-7 (IL-7) that are mechanistically associated with IL-7R expression differences that correlate with relative CD5 expression. Whereas CD5(hi) and CD5(lo) T cells survive equivalently in the presence of saturating IL-7 levels in vitro, CD5(hi) T cells proliferate more robustly. Conversely, CD5(lo) T cells exhibit prolonged survival when withdrawn from homeostatic stimuli. Through quantitative experimental analysis of signaling downstream of IL-7R, we find that the enhanced IL-7 responsiveness of CD5(hi) T cells is directly related to their greater surface IL-7R expression. Further, we identify a quantitative threshold in IL-7R-mediated signaling capacity required for proliferation that lies well above an analogous threshold requirement for survival. These distinct thresholds allow subtle differences in IL-7R expression between CD5(lo) and CD5(hi) T cells to give rise to significant variations in their respective IL-7-induced proliferation, without altering survival. Heterogeneous IL-7 responsiveness is observed similarly in vivo, with CD5(hi) naïve T cells proliferating preferentially in lymphopenic mice or lymphoreplete mice administered with exogenous IL-7. However, IL-7 in lymphoreplete mice appears to be maintained at an effective level for preserving homeostasis, such that neither CD5(hi) IL-7R(hi) nor CD5(lo) IL-7R(lo) T cells proliferate or survive preferentially. Our findings indicate that IL-7R-mediated signaling not only maintains the size but also impacts the diversity of the naïve T-cell repertoire.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD5 Antigens / genetics
  • CD5 Antigens / immunology
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Proliferation
  • Cell Survival / immunology
  • Cells, Cultured
  • Cytokines / immunology
  • Gene Expression Regulation
  • Homeostasis / drug effects
  • Homeostasis / immunology
  • Immunologic Factors / metabolism
  • Immunologic Factors / pharmacology
  • Interleukin-7 / metabolism
  • Interleukin-7 / pharmacology
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • Receptors, Interleukin-7 / genetics
  • Receptors, Interleukin-7 / immunology*
  • Signal Transduction / drug effects
  • Signal Transduction / immunology*


  • CD5 Antigens
  • Cytokines
  • Immunologic Factors
  • Interleukin-7
  • Receptors, Interleukin-7