EDITORIALBJD

British Journal of Dermatology

Personal reflections on 25 years of immunodermatology

DOI: 10.1111/bjd.13366

When I was invited by the British Association of Dermatolo-

gists to give the Rook Oration in 1999, the field of immuno-

dermatology was enjoying a time of rapid evolution. We had

just solved the structure of human cutaneous lymphocyte anti-

gen (CLA) 2 years previously,1 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 keratino-

cytes,2–6 culminating in the construction of transgenic mice

that overexpressed cytokines under the control of keratin pro-

moters,7–12 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, main-

taining 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.4 That an ‘activated epidermis’ could elabo-

rate factors that would recruit leucocytes had never been pre-

viously considered, as Langerhans cells were thought to be the

principal immunologically important cells in this tissue.13 We

learned over the following years that keratinocyte cytokines

could also influence the behaviour of dendritic cells, particu-

larly as they efficiently present antigen to T cells.10 By the late

1990s, the participation of keratinocytes and other ‘innate

immune’ cells in skin immunity had become accepted.6

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.14 In contrast, memory T cells destined for the gas-

trointestinal tract did not bear CLA, but expressed high levels of

the integrin a4b7 on their surface.15,16 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.14,17 Similarly, the vas-

cular addressin MAdCAM-1 (mucosal addressin cellular adhe-

sion molecule-1) is expressed by intestinal lamina propria

postcapillary venules – its ligand is integrin a4b7.18 Memory T

cells that are found in lung infiltrates, or home to lung from

blood, express neither CLA nor a4b7, although their distin-

guishing cell-surface profile is still a matter of debate.18 Other

work showed that the ‘imprinting’ of homing markers was tis-

sue specific; that is, naive T cells activated by antigen in skin-

draining 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.17 A narrative was constructed in which different popula-

tions 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-path-

ogen-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.4,17

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 immunocompro-

mised 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.19 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.20,21 At steady

state, the number of CLA+ cells in skin outnumbered those in

blood by > 50-fold.22 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 circulat-

ing T cells in this regard.22–24

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).25,26 Indeed, it appears that much of the T-cell mem-

ory against environmental pathogens may in fact reside in tis-

sues 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, autoreac-

tive 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

© 2014 British Association of Dermatologists684 British Journal of Dermatology (2014) 171, pp684–686

and even contact dermatitis may be mediated by aberrantly

activated TRM. Other T-cell-mediated skin diseases are likely to

involve TRM as well.

Of all the lessons I have learned from a career as a biomedi-

cal scientist in dermatology and immunology, the most

important is: be prepared to modify or abandon your para-

digms, no matter how closely held, if the experimental data

and clinical observations make them untenable. Embracing the

new and unexpected is one of the joys of our discipline. We

must remember that only recently the notion that keratino-

cytes could produce immunologically important cytokines was

never considered. The idea that memory T cells could express

cell-surface molecules that would guide them preferentially to

different tissues was, at one time, completely unexpected. And

the idea that T cells would remain in tissues and represent a

critically important compartment for host defence was simply

never considered until it was demonstrated experimentally.

Prior to our understanding that different subsets of memory T

cells had different homing properties, it would have been

impossible to classify mycosis fungoides as a malignancy of

skin TRM, and S�ezary syndrome as a malignancy of skin-hom-

ing TCM.27 Twenty-five years ago, psoriasis was a disease of

disordered keratinocyte proliferation. Ten years ago, it was a

disease mediated by type I, or interferon-c-producing, T cells,

and interleukin (IL)-12 was the critical cytokine. Today we

understand psoriasis to be an autoreactive disease mediated in

large part by T helper (Th)17 T cells, and IL-17, IL-22 and

IL-23 (related to IL-12, but a Th17 facilitator) are pivotal

cytokines. Paradigms evolve, and sometime shift completely,

in ways that no one can predict. In science, as in life, chance

favours the prepared mind. In all pursuits, if you follow

where the data lead you, you will never go wrong!

Conflicts of interest

None declared.

T .S . KUP P E RBrigham and Women’s Hospital, Harvard

Medical School, Boston, MA 02115, U.S.A.

E-mail: tkupper@partners.org

References

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lymphocyte antigen is a specialized form of PSGL-1 expressed onskin-homing T cells. Nature 1997; 389:978–81.

2 Kupper TS. Interleukin 1 and other human keratinocyte cytokines:molecular and functional characterization. Adv Dermatol 1988;

3:293–307.3 Kupper TS. Immune and inflammatory processes in cutaneous tis-

sues. Mechanisms and speculations. J Clin Invest 1990; 86:1783–9.4 Kupper TS, Fuhlbrigge RC. Immune surveillance in the skin:

mechanisms and clinical consequences. Nat Rev Immunol 2004;

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16 Picker LJ, Terstappen LW, Rott LS et al. Differential expression ofhoming-associated adhesion molecules by T cell subsets in man.

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lymphocyte homing. Annu Rev Immunol 1992; 10:561–91.19 Boyman O, Hefti HP, Conrad C et al. Spontaneous development of

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skin. J Invest Dermatol 2006; 126:1059–70.22 Clark RA. Skin-resident T cells: the ups and downs of on site

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cells do not recirculate and provide immune protection in ale-mtuzumab-treated CTCL patients. Sci Transl Med 2012; 4:117ra7.

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25 Kupper TS. Old and new: recent innovations in vaccine biologyand skin T cells. J Invest Dermatol 2012; 132:829–34.

26 Purwar R, Campbell J, Murphy G et al. Resident memory T cells(TRM) are abundant in human lung: diversity, function, and

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