Tolerogenic and immunogenic states of Langerhans cells are orchestrated by epidermal signals acting on a core maturation gene module

Abstract

Langerhans cells (LCs), residing in the epidermis, are able to induce potent immunogenic responses and also to mediate immune tolerance. We propose that tolerogenic and immunogenic responses of LCs are directed by signaling from the epidermis and involve counter-acting gene circuits that are coupled to a core maturation gene module. We base our analysis on recent genetic and genomic findings facilitating the understanding of the molecular mechanisms controlling these divergent immune functions. Comparing gene regulatory network (GRN) analyses of various types of dendritic cells (DCs) including LCs we integrate signaling-dependent (TGFβ, EpCAM, β-Catenin) and transcription factor (IRF4, IRF1, NFκB) regulated gene circuits that appear to orchestrate the distinctive LC functional states. Our model proposes, that while epidermal signaling in the steady-state promotes LC tolerogenic function, the disruption of cellcell contacts coupled with inflammatory signaling induces LC immunogenic programing. The conceptual framework emphasizes the sensing of discrete epidermal and inflammatory cues by resident LCs in dictating their genomic programing and cell state dynamics.

The Roles of Skin Langerhans Cells in Immune Tolerance and Cancer Immunity

“…Importantly, kynurenine metabolites, produced by IDO-mediated tryptophan catabolism, could augment AhR activity and sustain IDO expression, creating a positive feedback loop previously proposed to operate in other tolerogenic DC [122,125]. Thus, it has been proposed that a self-reinforcing control circuit involving the loss of EpCAMmediated LC:KC interactions; the induction of IRF4, ROCK2, and β-catenin signaling; and AhR activation could orchestrate a cell migration-coupled maturation program alongside a tolerance-inducing genomic module in LC [117].…”

“…Based on recent the genomic and epigenomic analyses of human LC and studies of other types of DC, Polak and Singh hypothesized that human LC tolerogenic and immunogenic states are directed through the counteraction of gene regulatory networks that are coupled to a shared core maturation gene module [117]. The authors proposed that the stability of this functionally specific transcriptional state is controlled by multiple positive and negative regulatory feedback loops.…”

“…During the infection of the epidermis, TLR and proinflammatory cytokine signaling override TGF-β signaling [126,127]. Polak and Singh have further hypothesized that proinflammatory signaling from pathogen-derived danger signals and activated KC induce an immunogenic LC transcriptional program regulated by IRF1 and NF-κB [117]. Notably, IRF1 and IRF4 have been shown to counter-regulate each other's functions in a variety of cellular contexts [128][129][130].…”

Understanding the tuberculosis granuloma: the matrix revolutions

“…One proposed paradigm is that a balance within granulomas is necessary, with both proinflammatory and anti-inflammatory mediators leading to control of infection [ 49 , 50 ]. With their pivotal role in orchestrating the immune response, dendritic cells are also likely to have a central role in shaping the immune response and defining outcome [ 51 ]. However, because these events occur within tissue, they are challenging to investigate, and studying the host response in the periphery is unlikely to convey sufficient granularity about individual lesions [ 52 ].…”

Current knowledge of immunomodulation strategies for chronic skin wound repair

“…Moreover, they usually play a significant role in autoimmune skin problems or allergic cases 36 . LCs are among the primary antigen present cells (APC) in the epidermis 37 . With the same function as keratinocytes, these cells can maintain the pro‐inflammatory process in the tissue by secreting inflammatory agents and expressing specific cellular receptors and are effective in the skin's immune system 38 …”