Induction of granzyme B and T cell cytotoxic capacity by IL-2 or IL-15 without antigens: Multiclonal responses that are extremely lytic if triggered and short-lived after cytokine withdrawal

• Published in: Cytokine (Philadelphia, Pa.) Vol. 36; no. 3; pp. 148 - 159
• Main Authors: Tamang, David L., Redelman, Doug, Alves, Bryce N., Vollger, Leanne, Bethley, Christy, Hudig, Dorothy
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.11.2006
• Subjects: Animals; Antigens, Differentiation, T-Lymphocyte - metabolism; CD11a Antigen - metabolism; CD2 Antigens - metabolism; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell activation; Cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; Cell Survival - immunology; Cells, Cultured; Cytokines; Cytotoxic; Cytotoxicity; Cytotoxicity Tests, Immunologic; Cytotoxicity, Immunologic - drug effects; Cytotoxicity, Immunologic - immunology; Flow Cytometry; Granzyme B; Granzymes - metabolism; Hyaluronan Receptors - metabolism; Inducible T-Cell Co-Stimulator Protein; Interleukin-15 - pharmacology; Interleukin-2 - pharmacology; Interleukin-2 Receptor beta Subunit - metabolism; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Mice; Mice, Inbred C57BL; Receptors, Immunologic - metabolism; Receptors, Natural Killer Cell; Spleen - cytology; T Cells; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; Cell proliferation; Cell activation; T Cells; Granzyme B; Cytokines; Cytotoxicity; Cytotoxic
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1016/j.cyto.2006.11.008

The purpose of these studies was to determine the minimal requirements to induce granzyme B, cytotoxic granules and perforin-dependent lytic capacity. To our surprise, both IL-2 and IL-15 induced not only proliferation, but also profound granzyme B and lytic capacity from CD8 + T cells in the absence of antigen or TCR-stimulation. Mouse splenocytes were incubated with mouse r-IL-2 or r-IL-15 for three days, tested by anti-CD3 redirected lysis and examined for intracellular granzyme B and for T cell activation markers. With 10 −8 M IL-2 or IL-15, there was excellent lytic activity at 1:1 effector to target ratios mediated by T cells from wild-type but not from perforin-gene-ablated mice, consistent with multiclonal activation. Lower interleukin concentrations induced less lytic activity. Granzyme B was undetectable on day 0, and greatly elevated on day 3 in CD44 hi CD8 + T cells as detected by flow cytometry. Cytokines alone elevated the granzyme B as much as concanavalin A combined with the cytokines. Some ex vivo CD8 + T cells were CD122 +, as were the cultured granzyme B + cells, thus both populations had low-affinity receptors for the interleukins. Only some of the activated cells were proliferating as detected by CFSE labeling. When the cytokines were withdrawn, the cells lost lytic activity within 24 h and then within the next 24 h, died. Our results suggest that high concentrations of either IL-2 or IL-15 will activate the lytic capacity and granzyme B expression of many T cells and that antigen recognition is not required.