Abstract
Langerhans cells (LCs) reside in the epidermis as a dense network of immune system sentinels. These cells determine the appropriate adaptive immune response (inflammation or tolerance) by interpreting the microenvironmental context in which they encounter foreign substances. In a normal physiological, “non-dangerous” situation, LCs coordinate a continuous state of immune tolerance, preventing unnecessary and harmful immune activation. Conversely, when they sense a danger signal, for example during infection or when the physical integrity of skin has been compromised as a result of a trauma, they instruct T lymphocytes of the adaptive immune system to mount efficient effector responses. Recent advances investigating the molecular mechanisms underpinning the cross talk between LCs and the epidermal microenvironment reveal its importance for programming LC biology. This review summarizes the novel findings describing LC origin and function through the analysis of the transcriptomic programs and gene regulatory networks (GRNs). Review and meta-analysis of publicly available datasets clearly delineates LCs as distinct from both conventional dendritic cells (DCs) and macrophages, suggesting a primary role for the epidermal microenvironment in programming LC biology. This concept is further supported by the analysis of the effect of epidermal pro-inflammatory signals, regulating key GRNs in human and murine LCs. Applying whole transcriptome analyses and in silico analysis has advanced our understanding of how LCs receive, integrate, and process signals from the steady-state and diseased epidermis. Interestingly, in homeostasis and under immunological stress, the molecular network in LCs remains relatively stable, reflecting a key evolutionary need related to tissue localization. Importantly, to fulfill their key role in orchestrating antiviral adaptive immune responses, LC share specific transcriptomic modules with other DC types able to cross-present antigens to cytotoxic CD8+ T cells, pointing to a possible evolutionary convergence mechanism. With the development of more advanced technologies allowing delineation of the molecular networks at the level of chromatin organization, histone modifications, protein translation, and phosphorylation, future “omics” investigations will bring in-depth understanding of the complex molecular mechanisms underpinning human LC biology.
Highlights
One of the most critical functions of the skin required by its role as the interface with the external environment, is to defend against microbial attack
Langerhans cells (LCs) are members of the dendritic cell (DC)/macrophage family, and they reside in the epidermis, forming a dense network with which potential invaders must interact
Cytokines released by keratinocytes in atopic dermatitis, e.g., thymic stromal lymphopoietin (TSLP), alter LC’s ability to induce adaptive immune responses [13, 14], while “homeostatic” cytokines, such as TGF-β, inhibit LC maturation in situ and are critical for LC retention in the epidermis [15, 16]
Summary
One of the most critical functions of the skin required by its role as the interface with the external environment, is to defend against microbial attack. The existing evidence indicates that, based on their transcriptome, LCs are distinct from both DCs and macrophages This supports the concept that the epidermal microenvironment acting on LC from the stage of an early progenitor cell plays a critical role in shaping LC biology and tailors it uniquely for the requirements of the tissue they populate. The epidermal derived cytokines TNF-α and TSLP altered the expression of genes associated with LC activation (CD40), antigen uptake and processing (CAV1, PSME1, PSME2, PSMB10), and antigen presentation (HLA-A, -B, -C, CIITA, HLA-DR), enhancing LC ability to activate antigen-specific adaptive immune responses and to cross-present antigens to CD8 T cells This model strongly supports the importance of antigen processing and presentation for LC function and provides a molecular explanation for regulation of LC immune programming by signals from the epidermis [13]. This clearly indicates, that the proposed IRF–GRN is only a part of a much bigger and more complex network of interactions, and needs to be further extended to model comprehensively immune activation versus tolerance in LCs
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