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Interferon-γ derived from cytotoxic lymphocytes directly enhances their motility and cytotoxicity
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Journal Article
Interferon-γ derived from cytotoxic lymphocytes directly enhances their motility and cytotoxicity
2017
Overview
Interferon gamma (IFN
γ
) is a key moderator of cell-mediated immunity with diverse, mainly pro-inflammatory actions on immunocytes and target tissue. Recent studies have shown it may enhance anti-tumor and antiviral effects of CD8 T cells. Here we investigate the mechanisms by which IFN
γ
mediates CD8 T-cell cytotoxic function. We show that
in vivo
, antigen-specific CD8 T cells that produce INF
γ
are necessary to effect rejection of skin grafts expressing OVA as a transgene in keratinocytes. The ability of CD8 T cells to produce IFN
γ
enhanced their ability to migrate to the site of antigen-presenting skin cells. By
in vivo
imaging, we show that CTL motility, particularly speed, during graft rejection was enhanced by locally available IFN
γ
. We then used a reductionist two-cell model of CTL effectors and keratinocyte targets to investigate the effects of locally available (paracrine) and CTL-producing (autocrine) IFN
γ
on the motility behavior and killing ability of the CTL. Using live-cell imaging by prolonged time-lapse microscopy of primary effector CD8 T cells and antigen-expressing primary keratinocyte targets, we show that CD8 T-cell cytotoxic function and motility is enhanced by locally available IFN
γ
. Conversely, deprivation of either autocrine or paracrine IFN
γ
, or blockade of IFN
γ
signaling to CTL markedly reduced their cytotoxic function, their kinematics, and effector cell survival. We conclude that
in vitro
and
in vivo,
autocrine production of IFN
γ
by CTL enhances their motility and promotes killing of primary target keratinocytes. The absolute need for local IFN
γ
to enable cytotoxic CD8 T-cell function is of significance for immunotherapy for chronic viral infection and for cancer.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 14
/ 14/69
/ 64/110
/ Animals
/ Autocrine Communication - immunology
/ Biomedical and Life Sciences
/ Graft Rejection - immunology
/ Interferon-gamma - biosynthesis
/ Interferon-gamma - deficiency
/ Interferon-gamma - immunology
/ Mice
/ Original
/ Paracrine Communication - immunology
/ T-Lymphocytes, Cytotoxic - cytology
/ T-Lymphocytes, Cytotoxic - immunology
/ T-Lymphocytes, Cytotoxic - secretion
