Fish requires FasL to facilitate CD8+ T-cell function and antimicrobial immunity

Although bony fish have CD8(+) T cells, the mechanisms by which these early-evolved cytotoxic cells combat intracellular pathogens remain unclear. In the present study, using Nile tilapia as a model, we investigated the detailed function, mechanism, and evolutionary pattern concerning CD8(+) T cells. By depleting CD8(+) T cells, they are found essential in combating Edwardsiella piscicida infection. Using siRNA interference, we propose that unlike the strategy predominantly relying on perforin/granzyme in mammals, CD8(+) T-cell effector function is mediated by both FasL and perforin/granzyme in fish. Upon E. piscicida infection, FasL is induced to express in CD8(+) T cells; both recombinant FasL and adoptively transferred FasL(+)CD8(+) T cells facilitate the apoptosis of target cells. Meanwhile, tilapia FasL also triggers the apoptosis of T cells to archive homeostasis. Since advances in mammals highlight the indispensable role of FasL in maintaining CD8(+) T-cell homeostasis, rather than in effector function or anti-infective immunity, we therefore propose the unique dual function of FasL in executing effector function and maintaining homeostasis in fish. Mechanistically, tilapia T cells utilize mTORC1/c-Myc axis to regulate pathogen-induced FasL expression, which binds to Fas and activates caspase-8/caspase-3 pathway, mediating apoptosis in target cells and T cells themselves. This represents a novel mechanism underpinning CD8(+) T-cell function in fish. Our findings demonstrate that CD8(+) T cells reshaped the FasL-dependent strategy throughout evolution, thereby enhancing the precision and specificity of adaptive immunity.