Skin immune surveillance by T cells—A new order?

Abstract

Although studies of the skin have provided fundamental models for innate and adaptive immune surveillance of body surfaces, there remains relatively little understanding of the role that epithelial cells play in sensing infection and/or organ dysfunction, and the pathways available to them to communicate with local and systemic immune cells. In particular, evidence is emerging for a novel stress response initiated by local lymphocytes, rather than dendritic cells, and based on their recognition of epithelial stress-induced antigens. Its consequences are to sustain tissue integrity by providing immunoprotection and novel modes of immunoregulation, whereas its dysregulation may promote body surface immunopathologies.

Introduction

Significant functions of mammalian skin include tactile sensation; physical, chemical, and secretory means of protection; thermo-, osmotic- and chemical-regulation; sensing of oxygen required for systemic responses to hypoxia; production of the precursor of vitamin D; and wound healing. Related to these, the skin is one of several surfaces widely cited as needing to provide a barrier against chronic engagement by microbial and other environmental insults [1]. Indeed, protective immunological mechanisms compose a key component of skin biology, and their study has provided instructive models that have been widely adopted in the context of immune surveillance at several other body surfaces [2]. However, unlike the gut or lung, human skin performs only minor absorptive functions, from which perspective the skin immune compartment may view any penetration of the epidermis as potentially harmful, and thereby respond in a less selective, more uncompromising way than the gut-associated immune compartment. This perceived potency of inductive immune responses in the skin has underpinned an increasing number of vaccine strategies that seek to deliver cocktails of antigens and adjuvants epi- or per-cutaneously.

Conversely, such powerful inductive and effector immune responses may explain the seemingly high vulnerability of the skin to allergic reactions. Indeed, there is an increasing view that the skin may be a common site for allergen sensitisation, even when the pathology is manifest in a different site, such as the airways. Allergic Th2-type responses characterise common and clinically confounding diseases such as atopic dermatitis (AD), where the unsuitability of prolonged steroid treatment, particularly in children, emphasises the urgent need for more research into skin immunity [3]. Likewise, there is still a pressing need for research into other common skin pathologies, such as psoriasis, that share more with Th1 or Th17-type responses [4], [5]. Because no specific auto-antigenic targets for T or B cells have been identified in AD or in psoriasis, it is premature to consider them autoimmune diseases, as opposed to inflammatory pathologies underpinned by hyperactive immune activity. This consideration emphasises the fact that skin integrity is jeopardised by host cells infiltrating from within, as much as by foreign agents and microbes penetrating from above.

In seeking to understand how the skin may respond to both types of dysregulation and dysfunction, it is essential to consider skin-resident myeloid-lineage cells, particularly dendritic cells (DC) that express numerous molecular sensors. Nonetheless, it may be argued that insufficient attention has been paid to epithelial cells themselves. Although their capacity to produce anti-microbial molecules and immunoregulatory cytokines and chemokines is well established, there is increasing interest in their capacity to sense dysregulation and to initiate a novel stress response pathway that involves the recognition of stress-induced epithelial surface antigens by tissue-associated lymphocytes. This manuscript will review the evidence for this against a backdrop of current perspectives on skin immunity, and will consider the implications for barrier immunity more generally.