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th R. Turnquist*
* Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213;
Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15213;
Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, United Kingdom; and
Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health (NIH) Grants R01AI41011 and R01AI60994 (to A.W.T.). H.R.T. was supported by nonconcurrent fellowships from the American Society of Transplantation and the NIH (T32CA082084 and F32AI072940). T.L.S. was supported by an NIH Research Training Fellowship (T32CA082084).
2 Address correspondence and reprint requests to Dr. Angus W. Thomson, Thomas E. Starzl Transplantation Institute, Department of Surgery, School of Medicine, University of Pittsburgh, 200 Lothrop Street, Biomedical Science Tower, W1540, Pittsburgh, PA 15213. E-mail address: thomsonaw{at}upmc.edu
3 Abbreviations used in this paper: RAPA, rapamycin; mTOR, mammalian target of rapamycin; Treg, regulatory T cell; DC, dendritic cell; mDC, myeloid DC; CTR, control; BM, bone marrow; IL-1Ra, IL-1 receptor antagonist; RPA, RNase protection assay; qRT-PCR, quantitative RT-PCR; sST2, soluble ST2; MFI, mean fluorescence intensity.
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