Granzyme K-expressing CD8⁺ T cells, complement activation and histotoxic immunity

Cytotoxic CD8⁺ T cells induce target-cell death by producing effector proteases called granzymes. Most granzymes, as exemplified by granzyme B, induce apoptosis by cleaving intracellular substrates after delivery to target cells via the immunological synapse. By contrast, it was recently shown that granzyme K (GZMK), which is selectively expressed by a unique population of CD8⁺ T cells, activates the complement cascade instead of executing direct cytotoxicity. In this Perspective, we summarize recent data on complement activation by CD8⁺ T cell-derived GZMK that points to a novel lymphocyte-mediated pathway of complement activation. We present evidence that GZMK-expressing CD8⁺ T cells have distinct pro-inflammatory effects in tissues and discuss their involvement in an array of chronic and inflammatory diseases. Furthermore, we propose the concept of 'tissue histotoxicity' as a core feature of GZMK-expressing CD8⁺ T cells. We suggest this as a defence strategy that enables the immune system to act on a tissue neighbourhood instead of targeting one cell at a time. Finally, we discuss the possibility of GZMK expression being a heritable trait in subsets of memory T cells.