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Low-strength T-cell activation promotes Th17 responses

Lookup NU author(s): Dr Jeroen Stoop, Professor Jelena Mann, Steven Woods, Anne Kozijn, Professor Sophie Hambleton, Professor John Robinson, Professor John Isaacs, Dr Amy Anderson, Dr Catharien Hilkens

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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-1 beta, transforming growth factor beta, 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 beta-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. (Blood. 2010;116(23):4829-4837)


Publication metadata

Author(s): Purvis HA, Stoop JN, Mann J, Woods S, Kozijn AE, Hambleton S, Robinson JH, Isaacs JD, Anderson AE, Hilkens CMU

Publication type: Article

Publication status: Published

Journal: Blood

Year: 2010

Volume: 116

Issue: 23

Pages: 4829-4837

Print publication date: 01/12/2010

ISSN (print): 0006-4971

ISSN (electronic): 1528-0020

Publisher: American Society of Hematology

URL: http://dx.doi.org/10.1182/blood-2010-03-272153

DOI: 10.1182/blood-2010-03-272153


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