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ST2L upregulation promotes maturation resistance in rapamycin‐conditioned dendritic cells
Author(s) -
Turnquist Heth Roderick,
Sumpter Tina L.,
Nau Gerard J.,
Thomson Angus W.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.862.9
Subject(s) - downregulation and upregulation , microbiology and biotechnology , dendritic cell , effector , receptor , biology , regulator , proximity ligation assay , immunology , immune system , gene , biochemistry
Objective: Maturation resistance and tolerogenicity can be conferred on dendritic cells (DC), ‐crucial regulators of T cells, by exposure to rapamycin (RAPA), a tolerance‐sparing immunosuppressant. The mechanisms underlying this acquired unresponsiveness, typified by diminished responses to Toll‐like receptor (TLR) ligation, have not been identified. Thus, our objective was to elucidate a molecular basis for RAPA‐induced DC maturation resistance. Methods: RAPA administration was used to condition splenic DC in vivo and bone‐marrow derived DC in vitro. DC maturation was monitored by assessment of co‐stimulatory molecule expression and allostimulatory capacity. To identify negative regulators of maturation, microarray analysis and quantitative RT‐PCR was completed, and findings confirmed via Western and flow cytometric analyses. Results: DC conditioning with RAPA promotes overexpression of the IL‐1 receptor(R) family member, ST2L, and enhances its surface expression. ST2L is the receptor for IL‐33 and has also been implicated as a negative regulator of TLR signaling. Consistent with this regulatory function, induced ST2L expression suppressed the responsiveness of RAPA‐DC to TLR ligation. Conclusion: This work identifies a novel mechanism by which a clinically‐important immunosuppressant impedes the capacity of DC to mature and consequently stimulate effector/adaptive T cell responses.