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Personal reflections on 25 years of immunodermatology

When I was invited by the British Association of Dermatologists to give the Rook Oration in 1999, the field of immunodermatology was enjoying a time of rapid evolution. We had just solved the structure of human cutaneous lymphocyte antigen (CLA) 2 years previously, and we were hard at work characterizing how the backbone of this structure, P selectin glycoprotein ligand-1, was glycosylated by T cells destined to home to skin. My work over the previous 15 years had been focused on the production of cytokines by epidermal keratinocytes, culminating in the construction of transgenic mice that overexpressed cytokines under the control of keratin promoters, demonstrating that in vivo, keratinocyte cytokines could mediate inflammation and leucocyte recruitment. In the early 1980s, keratinocytes were still regarded as little more than the complex bricks and mortar of the epidermis, maintaining the barrier function of skin. Over the next decade it became clear that these cells could also participate in immune and inflammatory responses by elaborating cytokines, then a revolutionary idea. That an ‘activated epidermis’ could elaborate factors that would recruit leucocytes had never been previously considered, as Langerhans cells were thought to be the principal immunologically important cells in this tissue. We learned over the following years that keratinocyte cytokines could also influence the behaviour of dendritic cells, particularly as they efficiently present antigen to T cells. By the late 1990s, the participation of keratinocytes and other ‘innate immune’ cells in skin immunity had become accepted. In 1990, T-cell trafficking was the new frontier. By this time, it became evident that cytokine profile was only one way to think about T-cell subset characterization. It was discovered that CLA was uniquely expressed on memory T cells in cutaneous infiltrates, as well as on T cells in blood that had skin-homing properties. In contrast, memory T cells destined for the gastrointestinal tract did not bear CLA, but expressed high levels of the integrin a4b7 on their surface. The vascular addressin E selectin is expressed constitutively on postcapillary venules in skin (and can be further upregulated by inflammation), and CLA was shown to be a principal ligand. Similarly, the vascular addressin MAdCAM-1 (mucosal addressin cellular adhesion molecule-1) is expressed by intestinal lamina propria postcapillary venules – its ligand is integrin a4b7. Memory T cells that are found in lung infiltrates, or home to lung from blood, express neither CLA nor a4b7, although their distinguishing cell-surface profile is still a matter of debate. Other work showed that the ‘imprinting’ of homing markers was tissue specific; that is, naive T cells activated by antigen in skindraining lymph nodes acquired CLA and other skin-homing markers, becoming ultimately skin-homing memory T cells. The converse was true for gut, wherein gut-draining lymphoid tissues would allow the generation of gut-homing memory T cells. A narrative was constructed in which different populations of organ-homing memory T cells circulated in blood, some of them circulating through their respective peripheral tissue, but all poised to enter their destination tissue when a pathogen was encountered. As tissue-homing molecules were acquired in the naive-to-memory transition in lymph nodes draining skin, gut and lung, skin-pathogen-specific T cells would be present in the CLA blood population, while gut-pathogen-specific T cells would be present in the a4b7 population. Once T cells were recruited into tissue to fight off the pathogen for which they were specific they would return to the blood. The first challenge to this paradigm came from the striking lack of efficacy of a clinical anti-E selectin antibody, which should have blocked extravasation of CLA skin-homing T cells in skin. Another report showed that nonlesional psoriatic skin, when grafted onto a unique strain of immunocompromised mice, would evolve T-cell-mediated psoriasis. This strongly suggested that the psoriasis-facilitating T cells were already in the nonlesional skin when it was grafted. Shortly thereafter, a series of landmark studies on human skin was published by Clark and colleagues, that in aggregate showed that human skin contained on the order of 20 billion T cells (twice as many as blood), and that these T cells had all the characteristics of CLA skin-homing T cells. At steady state, the number of CLA cells in skin outnumbered those in blood by > 50-fold. Over the next several years, these T cells would be referred to as ‘resident memory T cells’, or TRM. TRM are not simply T cells in an unexpected location; rather, both animal and human studies would show that they are primed for activity, and play a major role in host defence against previously encountered pathogens. Indeed, studies showed that these cells are much more effective than circulating T cells in this regard. Newer work is showing that skin is not unique – there are comparable large populations of TRM in the gut (where they express a4b7 instead of CLA) and lung (where they express neither). Indeed, it appears that much of the T-cell memory against environmental pathogens may in fact reside in tissues that are interfaces with the environment. This has two important implications. Firstly, vaccines against environmental pathogens should likely be designed to maximize generation of TRM in the appropriate barrier tissue. 25 Secondly, autoreactive T-cell-mediated diseases of barrier tissues, including many skin diseases, are likely to be mediated in large part by TRM. Indeed there is evidence that psoriasis, fixed drug eruption