Abstract
An effective cytotoxic T lymphocyte (CTL) response against intracellular pathogens is generally accomplished by immense CTL expansion and activation, which can destroy infected cells. Vigorous immune responses can lead to activation of bystander CD8+ T cells, but the contribution from antigen-specific CTLs is not well understood. We found that CTLs secrete extracellular vesicles following antigen stimulation. These CTL-derived vesicles contain CTL proteins and exhibit markers and size profiles consistent with exosomes. Interestingly, further stimulation of CTLs with IL-12 impacts exosome size and leads to selective enrichment of certain exosomal proteins. More important, exosomes from IL-12-stimulated CTLs directly activated bystander naïve CD8+ T cells to produce interferon-γ (IFNγ) and granzyme B (GZB) in the absence of antigens, whereas control exosomes derived from antigen-stimulated CTLs did not. In addition, IL-12 induced exosomes are able to strengthen the effects of weak antigen stimulation on CTLs. Proteomic analysis demonstrates that IL-12 stimulation alters catalytic and binding activities of proteins in CTL exosomes. Our findings indicate that the biological function and morphology of exosomes secreted by CTLs can be influenced by the type of stimulation CTLs receive. Thus, a fully functional, ongoing, antigen-specific CTL response may influence bystander CD8+ T cells through secretion of exosomes.
Highlights
One of the body’s primary responses to infection is the activation of cytotoxic T lymphocytes (CTLs), which undergo drastic expansion and become effectors that destroy pathogen-infected cells
The vesicles derived from 2SI-activated CTLs were larger than 3SI-conditioned CTL-derived vesicles (IL-12-exo), with mean sizes of 144 and 77 nm, respectively (Fig. 1A)
We discovered that the features of CTL-derived exosomes are associated with the type of stimulation the CD8+ T cells have received
Summary
One of the body’s primary responses to infection is the activation of cytotoxic T lymphocytes (CTLs), which undergo drastic expansion and become effectors that destroy pathogen-infected cells. Antigen-stimulated CD8+ T cells secrete exosomes that enhance the metastasis of melanoma cells to the lung via Fas signaling triggered by the exosome protein FasL20. It remains unknown if and how variations in CTL-derived exosome functions are associated with differences in CTL stimulation. We focused on CTL stimulation by the cytokine IL-12, which has been shown to be an important third signal cytokine in murine models[21,22] To test this hypothesis, we used OT-I transgenic CD8+ T cells in an in vitro system. Our results demonstrate that IL-12 induces structurally and functionally distinct activated CTL-derived exosomes, which can thereby activate bystander CD8+ T cells without the presence of antigen
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