IFN-γ, as Secreted during an Alloresponse, Induces Differentiation of Monocytes into Tolerogenic Dendritic Cells, Resulting in FoxP3+ Regulatory T Cell Promotion

Abstract

IFN-γ has been shown to inhibit monocyte (Mo) differentiation into mature dendritic cells (DC). Because IFN-γ also plays a role in tolerance induction, we asked whether this could be related to generation of tolerogenic DC (Tol-DC). Toward this aim, we cultured Mo with GM-CSF plus IL-4 in the presence or absence of IFN-γ for 6 days and induced their maturation with TNF-α for 2 additional days. We showed that IFN-γ deviated Mo differentiation from mature DC toward Tol-DC. Indeed, IFN-γ-generated DC 1) expressed moderate levels of costimulatory molecules, but high levels of Langerin and CD123 molecules, 2) were maturation resistant, and 3) were unable to efficiently present alloantigen to T cells. More interestingly, naive CD4+ T cells primed with IFN-γ-generated DC expressed FoxP3 mRNA at high levels and exerted regulatory functions upon secondary stimulation with alloantigen. To address whether endogenously secreted IFN-γ mediates a similar effect, we used the alloreaction as a model. We showed that cell-free supernatant harvested from an HLA-mismatched, but not HLA-identical, alloresponse induced differentiation of Mo into Tol-DC able to promote regulatory T cell generation. Moreover, when supplemented with GM-CSF plus IL-4, HLA-mismatched cell-free supernatant inhibited differentiation of Mo into mature DC. Finally, by adding Abs directed against inflammatory cytokines, we demonstrated that IFN-γ plays a preponderant role in this inhibition. In conclusion, our results clearly demonstrate that exogenous or endogenous IFN-γ, as well, induces differentiation of Mo toward Tol-DC, which results in FoxP3+ regulatory T cell promotion.

Human CD8+ T cells drive Th1 responses through the differentiation of TNF/iNOS‐producing dendritic cells

“…Interestingly, the inability of monocytes to express more TNF-a and iNOS after differentiation with a certain level of IFN-g suggests that a saturating effect occurs, thereby explaining why monocytes cultured with Supernatant CD8DC or Supernatant CD8DCLPS could both differentiate into Tip-DCs despite the latter having higher amounts of IFN-g and other cytokines. In contrast to our findings, previous groups have demonstrated that IFN-g skews monocytes toward macrophages [29] or tolerogenic DCs [30] instead. However, their results also revealed that IFN-g increases the expression of CD80, CD86 and CD40 as well as downregulation of phagocytosis, which are consistent with characteristics of Tip-DCs observed in our model.…”

Monocytic suppressive cells mediate cardiovascular transplantation tolerance in mice

“…Geissler and colleagues recently reported that differentiation of monocytes in the presence of IFN-γ results in the development of tolerogenic macrophages in vivo with T cell-suppressive function (67). Similar results have been obtained with human cells in vitro, in which IFN-γ mediated development of tolerogenic DCs from blood monocytes, with the ability to promote Treg development (68). We suggest that there may be at least 2 populations of tolerogenic monocytes that control the immune response: inflammatory Gr1 + monocytes that suppress antigen-nonspecific responses early after transplantation, and antiinflammatory Gr1 -monocytes that promote Treg development though PD-L1 expression.…”

Isolation of Human CD4/CD8 Double-Positive, Graft-Versus-Host Disease–Protective, Minor Histocompatibility Antigen–Specific Regulatory T Cells and of a Novel HLA-DR7–Restricted HY-Specific CD4 Clone

“…However, anti-IL-10 did not reverse our inhibitory effect (data not shown), suggesting IL-10 played no role in the regulatory activity. IFN-g has been shown by us and others to reduce T cell responses by inhibiting APC maturation (46) or by inducing inducible NO synthase production (47,48). However, in this study, this was excluded because IFN-g was secreted at low levels, and anti-IFN-g Ab did not block inhibition.…”