CD8 T cells lag behind their CD4 T cell counterparts in terms of cellular subsets and phenotypes. CD4 T cells are divided into populations including follicular and peripheral helper T cells (Tfh and Tph cells), regulatory T cells (Tregs), and Th1, Th2, and Th17 varieties of helper T cells [1,2]. Each population exerts well-defined effects on its cellular surroundings, and autoimmune diseases have been characterized by specific CD4 T cell subsets, such as Tph cells in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and Th17 cells in psoriasis [3,4].

CD8 T cells, on the other hand, are typically considered as either potent or exhausted cytotoxic effector cells or progenitors of these cells. Classic cytotoxic CD8 T cells, often referred to as cytotoxic T lymphocytes or CTLs, express large amounts of granzyme B (GzmB) and perforin, which enter target cells and induce apoptotic caspase cascades [5]. A growing literature has also uncovered a non-migratory tissue CD8 T cell population called resident memory T (Trm) cells, typically identified by expression of CD103 and CD69 [5,6]. However, recent studies have revealed that the most common CD8 T cell subset in tissues affected by autoimmune diseases does not clearly fall into any of these categories. Instead, the majority of CD8 T cells in RA synovial fluid and tissue express granzyme K (GzmK), a protease with different cleavage specificity that is unable to activate caspase cascades.

GzmK+ CD8 T cells can represent greater than 10% of all live cells in inflamed RA synovium and are also present in other autoimmune tissues [7], raising the question of how these cells contribute to the pathogenesis of autoimmune diseases. In this review, we will discuss GzmK+ CD8 T cells in autoimmune tissues and their possible functions in autoimmune inflammation.