IL-1beta-driven ST2L expression promotes maturation resistance in rapamycin-conditioned dendritic cells.
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-1beta by otherwise phenotypically immature DC. Interestingly, IL-1beta 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-1beta-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-1beta, 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.
Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Heth R
HR
Turnquist
Tina L
TL
Sumpter
Allan
A
Tsung
Alan F
AF
Zahorchak
Atsunori
A
Nakao
Gerard J
GJ
Nau
Foo Y
FY
Liew
David A
DA
Geller
Angus W
AW
Thomson
D000818:Animals; D051940:B7-2 Antigen / Q000378:metabolism; D001853:Bone Marrow / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology*; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D051940:B7-2 Antigen; D019013:CD40 Antigens; D053583:Interleukin-1beta; D017472:Receptors, Interleukin-1; C530318:ST2L protein, mouse; D051193:Toll-Like Receptors; D018808:Transcription Factor AP-1; D020123:Sirolimus