Low-strength T-cell activation promotes Th17 responses

HA Purvis, JN Stoop, J Mann, S Woods… - Blood, The Journal …, 2010 - ashpublications.org
HA Purvis, JN Stoop, J Mann, S Woods, AE Kozijn, S Hambleton, JH Robinson, JD Isaacs
Blood, The Journal of the American Society of Hematology, 2010ashpublications.org
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 …
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 Ca2+ ionophore under TLo conditions reversed the pro-Th17 effect, suggesting that high Ca2+ 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.
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