IRF4 in Dendritic Cells Inhibits IL-12 Production and Controls Th1 Immune Responses against Leishmania major

Abstract

IRF4 is a transcription factor from the IRF factor family that plays pivotal roles in the differentiation and function of T and B lymphocytes. Although IRF4 is also expressed in dendritic cells (DCs) and macrophages, its roles in these cells in vivo are not clearly understood. In this study, conditional knockout mice that lack IRF4 in DCs or macrophages were generated and infected with Leishmania major. Mice lacking DC expression of IRF4 showed reduced footpad swelling compared with C57BL/6 mice, whereas those lacking IRF4 in macrophages did not. Mice with IRF4-deficient DCs also showed reduced parasite burden, and their CD4+ T cells produced higher levels of IFN-γ in response to L. major Ag. In the draining lymph nodes, the proportion of activated CD4+ T cells in these mice was similar to that in the control, but the proportion of IFN-γ–producing cells was increased, suggesting a Th1 bias in the immune response. Moreover, the numbers of migrating Langerhans cells and other migratory DCs in the draining lymph nodes were reduced both before and postinfection in mice with IRF4 defects in DCs, but higher levels of IL-12 were observed in IRF4-deficient DCs. These results imply that IRF4 expression in DCs inhibits their ability to produce IL-12 while promoting their migratory behavior, thus regulating CD4+ T cell responses against local infection with L. major.

IRF4 and IRF8 Act in CD11c+ Cells To Regulate Terminal Differentiation of Lung Tissue Dendritic Cells

“…While a subset of CD11b + lung DCs expresses and depends on IRF4 expression as outlined above, our data show that numbers of CD11b + DCs in the dermis were not reduced by this same Irf4 deficiency. In fact, numbers of dermal CD11b + DCs were increased in CD11c-cre-Irf4 −/− mice, consistent with their inability to migrate to LN, as we and others observed previously (11, 25). While both pre-cDCs and monocytes were reported to give rise to lung and dermal CD11b + DCs, it is notable that lung CD11b + DCs were found to be much more dependent on Flt3L (29).…”

“…Mature DCs continue to express these transcription factors, which specify gene expression programs that direct their functional responses. IRF4-expressing DCs are important for the DC-driven polarization of T H 17 responses in the intestine and lung (6, 7), for the induction of T H 2 responses in lung allergy and skin parasite models (8–10) and for attenuation of T H 1 responses (11). In turn, IRF8-expressing DCs are often most important for T H 1 and CD8 + T cell responses, although the role of specific DC subsets is context dependent (12–16).…”

Pathogenic CD4 + T cells in patients with asthma

“…7 This molecule, which is modulated KLF4, directly targets the gene encoding the T H 2-promoting cytokine IL-33 ( Il33 ) while inhibiting production of the T H 1-differentiating cytokine IL-12 (Fig 1, A ). 7,8 The ability for house dust mite extract to upregulate IL-33 in mouse DCs through signaling through the C-type lectin receptor Dectin-2 suggests that allergen can trigger a similar process. 9 Additional T H 2-licensing stimuli include innate cytokines secreted by epithelial cells (eg, thymic stromal lymphopoietin [TSLP], IL-25, and IL-33), as well as IL-6 and the Notch ligand Jagged1, depending on the context.…”

Barrier Epithelial Cells and the Control of Type 2 Immunity

“…Although the exact DC subset initiating Th2 cell responses to helminths has not been formally identified yet, in the lung and in the skin, CD11b + CD172 (SIRP1a) + conventional (c)DCs that depend on the transcription factor IRF4 and KLF4 are necessary and sufficient to induce adaptive Th2-cell-associated immune responses (Akbari et al, 2014;Gao et al, 2013;Kumamoto et al, 2013;Plantinga et al, 2013;Tussiwand et al, 2015;Williams et al, 2013). The mechanisms by which these DCs induce Th2 cell immunity are poorly understood, compared with Th1, Th17, and T regulatory (Treg) cell responses, but several studies have shown the importance of the affinity of the major histocompatibility complex-T cell receptor (MHC-TCR) interaction, the tumor necrosis factor (TNF) ligand family member OX40L, the Notch ligand Jagged1, the cytokine IL-6, and the IRF4-induced absence of IL-12 production (Akbari et al, 2014;Amsen et al, 2004). Another reason why the initiation of Th2 cell immunity is so obscure is that DCs do not produce the polarizing IL-4 cytokine that drives Th2 cell immunity in many models.…”