Modulation of lytic molecules restrain serial killing in æ T lymphocytes

gamma delta T cells play a pivotal role in protection against various types of infections and tumours, from early childhood on and throughout life. They consist of several subsets characterised by adaptive and innate-like functions, with V gamma 9V delta 2 being the largest subset in human peripheral blood. Although these cells show signs of cytotoxicity, their modus operandi remains poorly understood. Here we explore, using live single-cell imaging, the cytotoxic functions of gamma delta T cells upon interactions with tumour target cells with high temporal and spatial resolution. While gamma delta T cell killing is dominated by degranulation, the availability of lytic molecules appears tightly regulated in time and space. In particular, the limited co-occurrence of granzyme B and perforin restrains serial killing of tumour cells by gamma delta T cells. Thus, our data provide new insights into the cytotoxic arsenal and functions of gamma delta T cells, which may guide the development of more efficient gamma delta T cell based adoptive immunotherapies. gamma delta T cells are unique T lymphocytes with cytotoxic functions, targeting infections and tumours. Here authors show that the target killing function of gamma delta T cells is tightly regulated at the level of the availability of lytic molecules granzyme B and perforin.