Tolerogenic signals delivered by dendritic cells to T cells through a galectin-1-driven immunoregulatory circuit involving interleukin 27 and interleukin 10

Abstract

Despite their central function in orchestrating immunity, dendritic cells (DCs) can respond to inhibitory signals by becoming tolerogenic. Here we show that galectin-1, an endogenous glycan-binding protein, can endow DCs with tolerogenic potential. After exposure to galectin-1, DCs acquired an interleukin 27 (IL-27)-dependent regulatory function, promoted IL-10-mediated T cell tolerance and suppressed autoimmune neuroinflammation. Consistent with its regulatory function, galectin-1 had its highest expression on DCs exposed to tolerogenic stimuli and was most abundant from the peak through the resolution of autoimmune pathology. DCs lacking galectin-1 had greater immunogenic potential and an impaired ability to halt inflammatory disease. Our findings identify a tolerogenic circuit linking galectin-1 signaling, IL-27-producing DCs and IL-10-secreting T cells, which has broad therapeutic implications in immunopathology.

Psoriasis in humans is associated with down‐regulation of galectins in dendritic cells

“…Most evidence pointing to gal-1 as a negative regulator of the immune response has been gathered in animal models of inflammatory diseases, and studies in human disease are comparatively scarce. Here, we demonstrate that psoriasis patients have low expression of gal-1 in peripheral blood myeloid DCs and in LCs of lesional and non-lesional skin that together with previous studies in animal models [34] indicate an important role of gal-1 in the immunopathogenesis of psoriasis. The positive role of gal-1 in IL-10 production has been proposed as one of the mechanisms involved in the inhibition of Th1 and Th17 responses [34][35][36] The co-culture experiments showed that galectin inhibition increases IFN-gamma production by CD4+ T cells in response to antigen presentation by DCs, suggesting that galectins also regulate the production of pro-inflammatory cytokines.…”

“…Galectin-1, either exogenously supplied or regulated endogenously, drove the differentiation of DCs toward a regulatory function, promoting T cell tolerance [34] [15]. Most evidence pointing to gal-1 as a negative regulator of the immune response has been gathered in animal models of inflammatory diseases, and studies in human disease are comparatively scarce.…”

Essential Role for IL-27 Receptor Signaling in Prevention of Th1-Mediated Immunopathology during Malaria Infection

“…Although the regulatory function of IL-27 is believed to be mediated in part via the induction of IL-10 secretion from CD4 + T cells (20)(21)(22)(23)(24)(25), and although we have shown that CD4 + T cell-derived IL-10 is essential for the prevention of severe liver pathology during P. yoelii infection (37), it is clear from the studies presented in this paper that IL-27 does not mediate its effects during malaria infection (both P. berghei and P. yoelii; data not shown) simply by inducing IL-10. Thus, although the outcome of P. berghei NK65 infection in IL-10 2/2 and WSX-1 2/2 mice is superficially very similar, their immune responses are quite different.…”

“…IL-10 2/2 and WSX-1 2/2 mice develop severe hepatic immunopathology during P. berghei NK65 infection through distinct immunological processes It has recently been reported that IL-27 can induce and/or enhance IL-10 production by CD4 + T cells (20)(21)(22)(23)(24)(25). Accordingly, our observation of lower IL-10 gene expression in CD4 + T cells in spleens and livers of infected WSX-1 2/2 mice when compared with WT mice (Figs.…”

“…IL-27 also promotes the production of IL-10 by various effector CD4 + T cell populations, including Th1 and Th2 cells and CD4 + T cells polarized under Th17-inducing conditions (20)(21)(22)(23)(24)(25). In line with these disparate roles, IL-27 signaling is essential for the generation of early protective T cell responses during Leishmania major (9) and bacillus Calmette-Guérin (8) infections but is required for the suppression of Th1-and Th17-mediated inflammation during Toxoplasma gondii, Trypanosoma cruzi, Mycobacterium tuberculosis, Leishmania donovani, and nonhealing L. major infections (17,(26)(27)(28)(29)(30)(31).…”