Niessl et al. found that blood-derived memory CD8+ T cells exhibited greater basal cytotoxic molecule expression than T cells from matched tissue, while resident memory cells exhibited the weakest cytotoxicity profile. Blood and tissue (tonsillar) effector memory CD8+ T cells also exhibited differential responses to TCR activation and cytokine stimulation (TGFβ/IL-15). Antigen specificity played a significant role in site residence and phenotype, wherein chronic virus-associated T cells exhibited greater cytotoxicity. While expression of diverse granzymes was considered a cytotoxic hallmark in blood T cells, only granzyme B was found to contribute to cell killing.
Contributed by Morgan Janes
ABSTRACT: CD8(+) T cells are classically defined by cytotoxic activity, but it has remained unclear whether cytotoxic programs are compartmentalized across tissues and memory subsets. Here, we established a human organ donor cohort and found that expression of conventional cytotoxic molecules-granulysin, perforin, and granzyme B-was most prominent among circulating memory CD8(+) T cells and decreased progressively with tissue residency, inversely mirroring the expression of CD69 and CD103. Other cytotoxic molecules, including granzymes A, H, K, and M, were variably expressed across tissues, and memory CD8(+) T cells targeting persistent viruses expressed multiple granzymes coordinately. In an in vitro tonsil system, transforming growth factor-_ induced discordant regulation of cytotoxic molecules and CD103. Combined with interleukin-15, this circuitry modulated proliferation and the acquisition of redirected killing activity via perforin and granzyme B. Our findings suggest that human memory CD8(+) T cell cytotoxicity is intricately regulated by environmental cues reflecting tissue location and antigen specificity.
Author Info: (1) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (2) Center for Infectious Medicine, Department of Medicine Huddinge,
Author Info: (1) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (2) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (3) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (4) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (5) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (6) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (7) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (8) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (9) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (10) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (11) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (12) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (13) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (14) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (15) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (16) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (17) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (18) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (19) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (20) Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (21) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (22) Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (23) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (24) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (25) Division of Infection and Immunity, Cardiff University School of Medicine, University Hospital of Wales, Cardiff, UK. (26) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (27) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (28) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (29) Division of Infection and Immunity, Cardiff University School of Medicine, University Hospital of Wales, Cardiff, UK. Systems Immunity Research Institute, Cardiff University School of Medicine, University Hospital of Wales, Cardiff, UK. (30) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (31) Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (32) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (33) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. (34) ME Transplantation, Karolinska University Hospital Huddinge, Stockholm, Sweden. Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden. (35) Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
