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

Author:
Luo, Yuchun, Cai, Xiangna, Liu, Sucai, Wang, Sen, Nold-Petry, Claudia A., Nold, Marcel F., Bufler, Philip, Norris, David, Dinarello, Charles A., Fujita, Mayumi
Source:
Proceedings of the National Academy of Sciences of the United States of America 2014 v.111 no.42 pp. 15178-15183
ISSN:
0027-8424
Subject:
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
Abstract:
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.
Agid:
1787609