Langerhans cells of the skin
Langerhans cells (LC) are tissue-resident macrophages that form a network of cells across the epidermis of the skin, but which have the ability to migrate from the epidermis to draining lymph nodes (LN).
Their location at the skin barrier suggests a key role as immune sentinels. However, despite decades of research, the role of LC in skin immunity is unclear; ablation of LC results in neither fatal susceptibility to skin infection nor overt autoimmunity due to lack of immune regulation. Our understanding of immune processes has traditionally been centered on secondary lymphoid organs as sites of lymphocyte priming and differentiation, which is exemplified by LC, initially defined as a paradigm for tissue dendritic cells that migrate to draining LN on maturation. But, more recently, an awareness of the importance of the tissue environment in shaping effector immunity has emerged. In this mini-review, we discuss whether our lack of understanding of LC function stems from our lymph node-centric view of these cells, and question whether a focus on LC as immune regulators in situ in the skin may reveal clearer answers about their function in cutaneous immunology.
Langerhans cells (LC) are a unique population of mononuclear phagocytes that are seeded from common macrophage precursors in the skin epidermis before birth (1) (and reviewed in this topic). They are highly conserved across vertebrate species (2, 3) and this, with their location at the interface with the environment, suggests the strategic importance of LC as immune sentinels at the skin barrier surface.
Traditionally, immunologists have focused on secondary lymphoid organs as the center of T cell immunity, assuming that instructions given during the priming of naïve T cells by migratory and resident dendritic cells (DC) were sufficient for differentiation and effector function by T cells recruited to peripheral sites of tissue injury. However, the field is beginning to appreciate importance of the tissue environment in regulating effector and regulatory T cell function, and it is clear that antigen-presenting cell-T cell interactions play a key role in T cell survival and function outside lymphoid organs (4). Despite sharing an origin with other tissue-resident macrophages, differentiation of LC is associated with the acquisition of DC-like functions, namely the ability to migrate to skin-draining lymph nodes (LN) and interact with naïve T cells. Observation of this property in the 1980s has dominated the field, and as a result, studies to define LC function in the skin have focused largely on their role as DC-like cells in priming T cell immunity [reviewed by Romani et al. (5)]. However, to date, a consistent role for LC as primers of T cell immunity has not emerged. In particular, there are few scenarios, if any, in which removal of LC ablates immunity to infection, or results in the development of severe autoimmunity in mice; and, despite the common observation that LC are sufficient to prime T cell immunity after the experimental provision of antigen and adjuvants that may favor LC activation and migration [e.g., Ref. (6)], few papers have explicitly identified a crucial role for migratory LC, and not dermal DC, under physiological conditions.
We suggest that shifting our focus to potential roles for LC in situ in the skin, a function more in keeping with their development as macrophages, will provide clearer answers about the importance of these unique cells in skin immunity. In this mini-review, we will consider the evidence for LC functions within the skin (Figure 1), and discuss whether our historic focus on LC as exemplars of migrating DC has skewed our understanding of their role in skin immunity.
https://www.frontiersin.org/articles/10.3389/fimmu.2017.01941/full#:~:text=Langerhans%20cells%20(LC)%20are%20a,key%20role%20as%20immune%20sentinels.