Low-strength T-cell activation promotes Th17 responses

Blood. 2010 Dec 2;116(23):4829-37. doi: 10.1182/blood-2010-03-272153. Epub 2010 Aug 16.

Abstract

We show that the strength of T-cell stimulation determines the capability of human CD4(+) T cells to become interleukin-17 (IL-17) producers. CD4(+) T cells received either high- (THi) or low (TLo)-strength stimulation via anti-CD3/CD28 beads or dendritic cells pulsed with superantigen in the presence of pro-Th17 cytokines IL-1β, transforming growth factor β, and IL-23. We found that TLo, but not THi, stimulation profoundly promoted Th17 responses by enhancing both the relative proportion and total number of Th17 cells. Titration of anti-CD3 revealed that low TCR signaling promoted Th17 cells, but only in the presence of anti-CD28. Impaired IL-17 production in THi cells could not be explained by high levels of Foxp3 or transforming growth factor β-latency-associated peptide expressed by THi cells. Nuclear factor of activated T cells was translocated to the nucleus in both THi and TLo cells, but only bound to the proximal region of the IL-17 promoter in TLo cells. The addition of a Ca(2+) ionophore under TLo conditions reversed the pro-Th17 effect, suggesting that high Ca(2+) signaling impairs Th17 development. Although our data do not distinguish between priming of naive T cells versus expansion/differentiation of memory T cells, our results clearly establish an important role for the strength of T-cell activation in regulating Th17 responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Differentiation / immunology*
  • Cell Separation
  • Chromatin Immunoprecipitation
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Humans
  • Lymphocyte Activation / immunology*
  • Male
  • Mice
  • Mice, Inbred DBA
  • Signal Transduction / immunology
  • Th17 Cells / cytology*
  • Th17 Cells / immunology