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Suppression of antigen-specific adaptive immunity by IL-37 via induction of tolerogenic dendritic cells

Luo, Yuchun, Cai, Xiangna, Liu, Sucai, Wang, Sen, Nold-Petry, Claudia A., Nold, Marcel F., Bufler, Philip, Norris, David, Dinarello, Charles A., Fujita, Mayumi
Proceedings of the National Academy of Sciences of the United States of America 2014 v.111 no.42 pp. 15178-15183
T-lymphocytes, adaptive immunity, contact dermatitis, dendritic cells, gene expression, humans, hypersensitivity, immune response, innate immunity, interleukin-1, lymph nodes, mice, migratory behavior, transgenic animals
IL-1 family member IL-37 limits innate inflammation in models of colitis and LPS-induced shock, but a role in adaptive immunity remains unknown. Here, we studied mice expressing human IL-37b isoform (IL-37tg) subjected to skin contact hypersensitivity (CHS) to dinitrofluorobenzene. CHS challenge to the hapten was significantly decreased in IL-37tg mice compared with wild-type (WT) mice (−61%; P < 0.001 at 48 h). Skin dendritic cells (DCs) were present and migrated to lymph nodes after antigen uptake in IL-37tg mice. When hapten-sensitized DCs were adoptively transferred to WT mice, antigen challenge was greatly impaired in mice receiving DCs from IL-37tg mice compared with those receiving DCs from WT mice (−60%; P < 0.01 at 48 h). In DCs isolated from IL-37tg mice, LPS-induced increase of MHC II and costimulatory molecule CD40 was reduced by 51 and 31%, respectively. In these DCs, release of IL-1β, IL-6, and IL-12 was reduced whereas IL-10 secretion increased (37%). Consistent with these findings, DCs from IL-37tg mice exhibited a lower ability to stimulate syngeneic and allogeneic naive T cells as well as antigen-specific T cells and displayed enhanced induction of T regulatory (Treg) cells (86%; P < 0.001) in vitro. Histological analysis of CHS skin in mice receiving hapten-sensitized DCs from IL-37tg mice revealed a marked reduction in CD8 ⁺ T cells (−74%) but an increase in Treg cells (2.6-fold). Together, these findings reveal that DCs expressing IL-37 are tolerogenic, thereby impairing activation of effector T-cell responses and inducing Treg cells. IL-37 thus emerges as an inhibitor of adaptive immunity.