T cells in tissue stress-surveillance and cancer

Our body surfaces, such as skin, gut and lung, are our major barriers to myriad infectious agents and toxic chemicals that populate the outside world. For the most part, those barriers have been considered to be physical and chemical in nature. However, our and others’ work have shown that body surfaces are rich in T lymphocytes (a specialised kind of immune cell), particularly a subtype known as gamma delta (??) T cells, that we were instrumental in discovering. We have shown that these ?? cells can respond rapidly to changes in the status of body surfaces, including a capacity to distinguish cancer from normal cells. Hence ?? cells may have profound clinical utility. However, to develop this potential, we need to understand the molecular pathways by which ?? cells distinguish normal from dysregulated tissues, thereby responding in an ordered and effective fashion. In this regard, we have recently identified key molecules, known as butyrophilins, that body surface cells use to communicate with their local ?? cell compartments. The study of these molecules provides a promising experimental route by which to understand this natural immune surveillance system.

This work was supported by the Francis Crick Institute which receives its core funding from the UK Medical Research Council (FC001000), the Wellcome Trust (FC001000),and Cancer Research UK (FC001000)

Body surfaces provide protection and integrity to metazoans, but are also primary sites of infection, inflammatory pathologies and cancer. In mice, body surface immune systems are extensively populated by T cell receptor (TCR)??+ lymphocytes that rapidly respond en masse to local dysregulation. Hence, their implication in wound-healing, inflammation and cancer. However, the existence of analogous immunosurveillance in humans was unresolved. By application of newly-developed methods for the visualisation, isolation, and characterisation of human tissue-associated T cells, we recently identified large tissue-resident??? compartments in human skin, gut and breast, and showed that they were able to respond rapidly to epithelial cells with dysregulated Epidermal Growth Factor Receptor signalling, a very common feature of infection, inflammation, and cancer. Moreover, we showed that ?? cells acquire this innate-like responsiveness during their development, whereupon they transition away from the adaptive biology of conventional T cells. For signature, murine, intra-epidermal V?5V?1+ cells this transition coincides with the cells’ selective differentiation and expansion driven by Skint1, an epithelial butyrophilin-like (Btnl) gene that we and our colleagues identified as the first “selecting element” for a major tissue-associated ?? compartment. Thereafter, we have found that Skint1 sustains immunosurveillance by orchestrating steady-state?interation between keratinocytes and mature V?5V?1+ cells. Recently we discovered that Skint2 is also required for intra-epidermal V?5V?1+ cells, suggesting that skin ?? cells are regulated by Skint1-Skint2 heteromers. Importantly, these lessons are proving generalizable. Thus, we have shown that the signature, murine V?7+ gut compartment depends on Btnl1, which together with Btnl6, specifically regulates mature V?7+ gut cells. Likewise, by applying our newly-developed methods for studying human T cells from healthy and diseased biopsies and resections, we have found that BTNL3+BTNL8 jointly regulate human gut ?? cells. Moreover, by extending others’ work, we have found that BTN3A1+BTN3A2 regulate peripheral blood ?? cells. By identifying the regulators of ?? cells, our findings offer new perspectives into body surface immunology. In particular, how do epithelial cells use BTNL/Btnl proteins to communicate information about the status of tissues that may merit immunosurveillance? Those perspectives may begin to explain the extremely strong correlation of tumour-associated ?? signatures with overall survival, reported in 18,000 cancer patients. Moreover, our methods for expanding very large numbers of human ?? cells, supported by genetic validation experiments in mice, may offer novel practical modalities of immunotherapy for cancer and inflammatory diseases. To this end, we have undertaken NIHR-supported pilot studies leading to the establishment of a start-up company named GammaDelta Therapeutics.