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

Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15178-83. doi: 10.1073/pnas.1416714111. Epub 2014 Oct 7.

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.

Keywords: allergic contact dermatitis; skin inflammation; tolerance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptive Immunity*
  • Animals
  • CD8-Positive T-Lymphocytes / cytology
  • Cell Movement
  • Chemotaxis
  • Cytokines / metabolism
  • Dendritic Cells / cytology*
  • Dermatitis, Contact / immunology
  • Dinitrofluorobenzene / chemistry
  • Flow Cytometry
  • Haptens / chemistry
  • Humans
  • Immunity, Innate
  • Interleukin-1 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phagocytosis
  • Skin / metabolism
  • T-Lymphocytes, Regulatory / cytology

Substances

  • Cytokines
  • Haptens
  • IL37 protein, human
  • Interleukin-1
  • Dinitrofluorobenzene