Gut Gamma Delta T cells detected by their expression of TCR delta chain RNA (red) line the human colonic epithelium (DAPI; blue) where they are well-placed to perform frontline immune surveillance.

Adrian Hayday : Epithelial cell regulators of T cells at body surfaces

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Immunology is undergoing major upheavals. Traditionally considered a means to fight infection, it is increasingly accepted to recognise wide-ranging dysregulation, including cell transformation. Likewise, whereas the most commonly studied immune cells are in the systemic circulation, we have pursued the study of T lymphocytes that reside in very large numbers in the skin and gut.

Occupying the front line, such intraepithelial lymphocytes (IEL) have long been hypothesised to provide a first line of defense, responding to molecular cues of stress expressed by neighbouring epithelial cells.

Recently, we identified the first examples of epithelial molecules that directly regulate IEL under normal circumstances, holding them in an activated-yet-resting state. Likewise, we have elucidated molecules and mechanisms permitting such T cells to respond in rapid yet regulated ways to tissue disruption, by comparison to the traditional, delayed responses of systemic T cells.

These data offer fresh insights into some paradoxes regarding tumour immune-surveillance.

Epithelial cell regulators of T cells at body surface

In 2011-2012 we showed that when intraepithelial skin T cells utilise their activating receptor, NKG2D, to engage Rae-1, an MHC class I-like molecule upregulated on physically-stressed tissue, the response leads rapidly to IgE production, most commonly associated with allergies (Strid et al., 2011; Science. 334(6060): 1293-7). This evoked a 20-year old hypothesis that IgE promotes the expulsion of toxins, preventing their systemic dissemination, and thereby protecting tissues.

In 2013 we prioritised our efforts in understanding how such a potent, IEL-initiated response is regulated. By specialised confocal microscopy of unperturbed mouse skin, we confirmed that the T cell receptor - the defining surface molecule of IEL - is anchored to specific contact-points of neighbouring epithelial cells, that we have now shown to be dependent on at least two immunoglobulin-like epithelial proteins, Skint1 and Skint2. Upon stress, such as ultraviolet light or physical abrasion, Skint1 expression declines and the contact-points break, freeing the T cells to respond to Rae-1.

As we seek a more complete biological picture of this novel form of epithelial cell-mediated immune regulation, one can consider that dysregulation of Skint1 might be a means for tumours or virus-infected cells to confound the capacity of IEL to distinguish dysregulation state from normality.

We are actively seeking a counterpart to Skint1, expressed by intestinal epithelial cells and potentially responsible for regulating particular subsets of gut IEL at steady state. Such a molecule would have implications for gut inflammation which is a common predisposing condition for bowel cancer.

Because we conduct parallel clinic-based investigations at Guy's Hospital, we can promptly investigate to what degree analogous molecules and mechanisms operate in the human skin and gut.

T cell regulators of T cells within tissues and tumours

The steady-state engagement of IEL by epithelial cells suggests that they are 'set up differently' from systemic T cells. Supporting this perspective, we have identified two distinct molecules, one cytosolic and one nuclear, that have no obvious effect on systemic T cells, but which regulate, respectively, the strength of the response of intestinal IEL to stress, and the types of cytokines that the responding IEL produce.

Our studies are aimed at understanding the mechanisms by which such molecules exert control of these fundamental pathways activated. By examining mice mutant in these molecules, we are also examining the pathophysiological consequences of losing these two components of IEL regulation, particularly in relation to gut inflammation.

Importantly, the distinct regulation of T cells within tissues questions the conventional perspective of viewing Tumour-Infiltrating Lymphocytes (TILs) merely as systemic lymphocytes temporarily interloping into a tissue (the tumour). We instead consider that TILs may be regulated as are tissue-resident IEL.

This perspective may explain the common observation that TILs appear suppressed: however, rather than this being imposed by the tumour, it may reflect the collective impacts of the intrinsic and epithelial-mediated regulators of IEL that we have identified. To test this, we have developed a novel protocol for obtaining TILs in large numbers and in good condition from primary human breast cancers, and are examining them for specific regulatory molecules and pathways.

Learning surveillance

The T cell receptor provides a fundamental checkpoint control over the appropriateness of a T cell response. Thus, if a conventional T lymphocyte engages cytokines and/or NKG2D ligands in the absence of T cell receptor engagement, the cell is inactivated so as to avoid the expansion of potentially auto-reactive cells. And yet, we and others have shown that many T cells compose compartments that respond very rapidly to signatory cytokines and stress-ligands expressed by stressed tissues (Strid et al., 2008; Nature Immunology. 9(2): 146-54).

Such innate-like T cells massively expand our view of lymphocytes since their biology involves lymphocytes in early decision-making events ordinarily assigned to innate immunity. This year we showed how this can be achieved: during the cells' thymic development, the T cell receptor pathway is engaged and then revised, so that it loses its primary regulation over the T cells in the periphery (Wencker et al., 2014; Nature Immunology. 15(1):80-7). Validating these criteria, we were able to use them to identify a novel innate-like T cell subset that may contribute to lymphoid stress-surveillance.