Human yeast-specific CD8 T lymphocytes show a nonclassical effector molecule profile

Abstract

Pathogenic yeast and fungi represent a major group of human pathogens. The consequences of infections are diverse and range from local, clinically uncomplicated mycosis of the skin to systemic, life-threatening sepsis. Despite extensive MHC class I-restricted frequencies of yeast-specific CD8 T lymphocytes in healthy individuals and the essential role of the cell-mediated immunity in controlling infections, the characteristics and defense mechanisms of antifungal effector cells are still unclear. Here, we describe the direct analysis of yeast-specific CD8 T lymphocytes in whole blood from healthy individuals. They show a unique, nonclassical phenotype expressing granulysin and granzyme K in lytic granules instead of the major effector molecules perforin and granzyme B. After stimulation in whole blood, yeast-specific CD8 T cells degranulated and, upon cultivation in the presence of IL-2, their granula were refilled with granulysin rather than with perforin and granzyme B. Moreover, yeast-specific stimulation through dendritic cells but not by yeast cells alone led to degranulation of the effector cells. As granulysin is the only effector molecule in lytic granules known to have antifungal properties, our data suggest yeast-specific CD8 T cells to be a nonclassical effector population whose antimicrobial effector machinery seems to be tailor-made for the efficient elimination of fungi as pathogens.

T cell responses to control fungal infection in an immunological memory lens

“…Oral immunization of mice with C. albicans under B-cell deficiency induced systemic memory of CD8 + T cells and provided protection following the challenge ( 120 ). The screening of Candida -specific memory CD8 + T cells in healthy human blood donors showed a non-classical cytotoxic molecules expression profile, i.e., secretion of granulysin and granzyme K rather than perforin/granzyme B ( 121 ). The CD8 + T cells were reactive to C. albicans , Candida glabrata , and Sporothrix and expressed lysosomal degranulation markers, CD107a/b, and secreted IFNγ and TNFα, following ex vivo stimulation with yeast-loaded dendritic cells.…”

“…Cytotoxic functions of T cells are well documented for CD8 + T cells. Antifungal CD8 + T cells deploy several antimicrobial granules (mainly granulysin and granzyme K) ( 121 ) for direct cytotoxic activity against the fungal pathogen or fungus-infected cells ( 218 , 219 ). Granzymes can mediate cell death by induction of active caspases, generation of ROS, and mitochondrial damage, while perforin may facilitate their release from the endosomes ( 220 ).…”

Immune Cell Degranulation in Fungal Host Defence

“…Currently, it has been shown that CD8+ T cells use granulysin, a pore-forming antimicrobial molecule, to kill C. neoformans [ 49 ]. In addition, yeast specific CD8+ T cells show a non-classical expression of granulysin and granzyme K instead of the classical perforin and granzyme B cytotoxic granule profile [ 88 ]. The mechanics of the granule-mediated cytotoxic activity by CD8+ T cells against fungal targets has not been explored.…”