Switching between tolerance and immunity: Do counter‐acting gene networks dictate Langerhans cell function in the skin?

Abstract

Immune responses must be carefully regulated at barrier sites such as the skin to ensure that we respond to infection, but not the daily innocuous insults that may enter the body. Langerhans cells (LC) are a unique population of antigen presenting cells that form a contiguous network throughout the outer epidermal layer of the skin.[1] However, despite their discovery in the 19th century, and the remarkable conservation of LC from zebrafish to mice and men, our understanding of the role LC play in the balance of skin immunity remains opaque. This ambiguity stems partly from the fact that LC canmigrate out of the epidermis to draining lymph nodes (LN) to prime naïve T cells.[2] But dendritic cells (DC), the professional antigen presenting cells of the dermis, are sufficient to activate T cell responses tomost cutaneous infections. These and other findings have led to the emergence of the dominant concept in recent years that LC may be more important for regulating T cell responses to harmless antigens in the skin. In this case, themajor outstandingquestion challenging the field is:what is it about LCbiology compared to dermal DC populations that favors the induction of T cell tolerance? In this issue of BioEssays, Polak and Singh have sought to provide insight into this question by considering the unique tethering of LC within epidermal keratinocytes, and the signals derived from the cellular attachments formed therein.[3] Bringing a unique perspective from their previous work using genomic and epigenetic analysis of primary human LC,[4] they hypothesize that the existence of LC in “tolerogenic” or “immunogenic” states is determined by counter-acting gene regulatory modules. These are linked to the disruption of cell contacts in the epidermis via a shared core activation/maturation gene module.[3] This hypothesis is centered on the proposed pivotal roles played by interferon regulatory factors (IRF), previously shown by the authors and others to play key roles in the T cell-stimulatory properties of DC and LC. Thus, they posit that in healthy skin loss of contact with the epidermis leads to upregulation of IRF4, which acts as a master switch to maintain expression of a tolerogenic gene program. They further hypothesize that inflammation and infection leads to the TNFα-dependent activation of the related factor, IRF1, which counteracts the IRF4-dependent gene program and takes over control of LC, which are now proficient at initiating T cell immunity upon arrival in the LN. The exciting nature of this hypothesis lies in the concept that