IL-1 β-driven ST2L express ion promotes maturation resistance in rapamycin-conditioned dendritic cells

Turnquist, H. R., Sumpter, T. L., Tsung, A., Zahorchak, A. F., Nakao, A., Nau, G. J., Liew, F. Y., Geller, D. A. and Thomson, A. W. (2008) IL-1 β-driven ST2L express ion promotes maturation resistance in rapamycin-conditioned dendritic cells. Journal of Immunology, 181(1), pp. 62-72.

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Publisher's URL: http://www.jimmunol.org/content/181/1/62.full

Abstract

Maturation resistance and tolerogenic properties can be conferred on human and murine dendritic cells (DC), crucial regulators of T cell responses, by exposure to rapamycin (RAPA), a “tolerance-sparing” immunosuppressive agent. Mechanisms underlying this acquired unresponsiveness, typified by diminished functional responses to TLR or CD40 ligation, have not been identified. We report that in vitro and in vivo conditioning of murine myeloid DC with RAPA elicits the de novo production of IL-1β by otherwise phenotypically immature DC. Interestingly, IL-1β production promotes overexpression of the transmembrane form of the IL-1R family member, IL-1R-like 1, also know as ST2 on RAPA-conditioned DC (RAPA-DC). ST2 is the recently identified receptor for IL-33, a cytokine favoring Th2 responses. In addition, transmembrane ST2, or ST2L, has been implicated as a potent negative regulator of TLR signaling. RAPA-DC generated from ST2−/− mice exhibited higher levels of costimulatory molecules (CD86) than wild-type RAPA-DC. Consistent with its regulatory function, IL-1β -induced ST2L expression suppressed the responsiveness of RAPA-DC to TLR or CD40 ligation. Thus, as a result of their de novo production of IL-1β, RAPA-DC up-regulate ST2L and become refractory to proinflammatory, maturation-inducing stimuli. This work identifies a novel mechanism through which a clinically important immunosuppressant impedes the capacity of DC to mature and consequently stimulate effector/adaptive T cell responses.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Liew, Prof Foo
Authors: Turnquist, H. R., Sumpter, T. L., Tsung, A., Zahorchak, A. F., Nakao, A., Nau, G. J., Liew, F. Y., Geller, D. A., and Thomson, A. W.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Immunology
Journal Abbr.:J. Immunol.
Publisher:American Association of Immunologists
ISSN:0022-1767
ISSN (Online):1550-6606
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
380241Toll-like receptors on T cellsFoo LiewMedical Research Council (MRC)G9818261/69296Infection Immunity and Inflammation Medicine