Abstract
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 CD44hi 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 When the cytokines were withdrawn, the cells lost lytic activity within 24 h and then within the next 24 h, died.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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Differentiation, T-Lymphocyte / metabolism
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CD11a Antigen / metabolism
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CD2 Antigens / metabolism
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Cell Survival / immunology
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Cells, Cultured
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Cytotoxicity Tests, Immunologic
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Cytotoxicity, Immunologic / drug effects*
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Cytotoxicity, Immunologic / immunology
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Flow Cytometry
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Granzymes / metabolism*
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Hyaluronan Receptors / metabolism
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Inducible T-Cell Co-Stimulator Protein
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Interleukin-15 / pharmacology*
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Interleukin-2 / pharmacology*
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Interleukin-2 Receptor beta Subunit / metabolism
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / immunology
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Mice
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Mice, Inbred C57BL
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Receptors, Immunologic / metabolism
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Receptors, Natural Killer Cell
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Spleen / cytology
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T-Lymphocytes / drug effects*
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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T-Lymphocytes, Cytotoxic / drug effects
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Cytotoxic / metabolism
Substances
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Antigens, Differentiation, T-Lymphocyte
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CD11a Antigen
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CD2 Antigens
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Cd44 protein, mouse
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Hyaluronan Receptors
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Icos protein, mouse
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Il2rb protein, mouse
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Inducible T-Cell Co-Stimulator Protein
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Interleukin-15
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Interleukin-2
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Interleukin-2 Receptor beta Subunit
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Receptors, Immunologic
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Receptors, Natural Killer Cell
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Granzymes
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Gzmb protein, mouse