Title: T cells in tissue stress-surveillance and cancer
Funder: The Francis Crick Institute

Abstract: 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.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;INFLAMMATORY AND IMMUNE SYSTEM