Antigen-Specific CD8 T Cells Can Eliminate Antigen-Bearing Keratinocytes with Clonogenic Potential via an IFN-γ-Dependent Mechanism

Kluyver, Rachel L. de; Moritz, Linnea; Harris, Chas. K.; Azukizawa, Hiroaki; Frazer, Ian H.

doi:10.1038/jid.2010.49

Cited by 3 publications

(3 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Given that their primary aim in inflammatory tissues is elimination of virally infected cells, lysis of cells presenting target antigen is crucial to their function. CD8 + T cell mediated apoptosis of keratinocytes is MHC class I restricted [17], and can be effected by processing and presentation of antigens by CD8 + T cells themselves [18]. We find that the process of killing of primary keratinocytes presenting physiological levels of non-self antigen is very slow, in contrast to tumor models and cell lines where killing has been reported within minutes to hours [19].…”

Section: Discussionmentioning

confidence: 79%

The Kinematics of Cytotoxic Lymphocytes Influence Their Ability to Kill Target Cells

et al. 2014

Self Cite

View full text Add to dashboard Cite

Cytotoxic lymphocytes (CTL) have been reported to show a range of motility patterns from rapid long-range tracking to complete arrest, but how and whether these kinematics affect their ability to kill target cells is not known. Many in vitro killing assays utilize cell lines and tumour-derived cells as targets, which may be of limited relevance to the kinetics of CTL-mediated killing of somatic cells. Here, live-cell microscopy is used to examine the interactions of CTL and primary murine skin cells presenting antigens. We developed a qualitative and quantitative killing assay using extended-duration fluorescence time-lapse microscopy coupled with large-volume objective software-based data analysis to obtain population data of cell-to-cell interactions, motility and apoptosis. In vivo and ex vivo activated antigen-specific cytotoxic lymphocytes were added to primary keratinocyte targets in culture with fluorometric detection of caspase-3 activation in targets as an objective determinant of apoptosis. We found that activated CTL achieved contact-dependent apoptosis of non-tumour targets after a period of prolonged attachment – on average 21 hours – which was determined by target cell type, amount of antigen, and activation status of CTL. Activation of CTL even without engagement of the T cell receptor was sufficient to mobilise cells significantly above baseline, while the addition of cognate antigen further enhanced their motility. Highly activated CTL showed markedly increased vector displacement, and velocity, and lead to increased antigen-specific target cell death. These data show that the inherent kinematics of CTL correlate directly with their ability to kill non-tumour cells presenting cognate antigen.

show abstract

Section: Discussionmentioning

confidence: 79%

The Kinematics of Cytotoxic Lymphocytes Influence Their Ability to Kill Target Cells

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…Rejection of K14E7 skin grafts is mediated by antigen-specific host cytotoxic CD8 + T cells (33), suggesting that excessive IL-17 production in the hyperplastic graft locally inhibits host cytotoxic effector T cell functions. In line with this, some studies have reported immune regulatory functions of IL-17 in epithelial diseases.…”

Section: Discussionmentioning

confidence: 99%

IL-17 Suppresses Immune Effector Functions in Human Papillomavirus-Associated Epithelial Hyperplasia

Gosmann

Mattarollo

Bridge

et al. 2014

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Persistent infection with high-risk human papillomaviruses (HPV) causes epithelial hyperplasia that can progress to cancer, and is thought to depend on immunosuppressive mechanisms that prevent viral clearance by the host. IL-17 is a cytokine with diverse functions in host defense and in the pathology of autoimmune disorders, chronic inflammatory diseases and cancer. We analyzed biopsies from patients with HPV- associated cervical intraepithelial neoplasia (CIN) grade 2/3 and murine skin displaying HPV16 E7 protein-induced epithelial hyperplasia, which closely models hyperplasia in chronic HPV lesions. Expression of IL-17 and IL-23, a major inducer of IL-17, was elevated in both human HPV-infected and murine E7-expressing lesions. Using a skin grafting model, we demonstrated that IL-17 in HPV16 E7 transgenic skin grafts inhibited effective host immune responses against the graft. IL-17 was produced by CD3+ T cells, predominantly CD4+ T cells in human, and CD4+ and γδ T cells in mouse hyperplastic lesions. IL-23 and IL-1β, but not IL-18, induced IL-17 production in E7 transgenic skin. Together, these findings demonstrate an immunosuppressive role for IL-17 in HPV-associated epithelial hyperplasia and suggest that blocking IL-17 in persistent viral infection may promote antiviral immunity and prevent progression to cancer.

show abstract

“…In skin, IFN γ appears to be essential to promoting T-cell migration to sites of inflammation, even in sterile conditions. 24, 25 We have shown IFN γ to be essential in mediating rejection of skin grafts expressing ovalbumin, 26 but it is suppressive of CD8 T-cell function when other antigens are expressed. 27 …”

mentioning

confidence: 99%

Interferon-γ derived from cytotoxic lymphocytes directly enhances their motility and cytotoxicity

et al. 2017

View full text Add to dashboard Cite

Interferon gamma (IFNγ) 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 IFNγ mediates CD8 T-cell cytotoxic function. We show that in vivo, antigen-specific CD8 T cells that produce INFγ are necessary to effect rejection of skin grafts expressing OVA as a transgene in keratinocytes. The ability of CD8 T cells to produce IFNγ 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 IFNγ. 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) IFNγ 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 IFNγ. Conversely, deprivation of either autocrine or paracrine IFNγ, or blockade of IFNγ 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 IFNγ by CTL enhances their motility and promotes killing of primary target keratinocytes. The absolute need for local IFNγ to enable cytotoxic CD8 T-cell function is of significance for immunotherapy for chronic viral infection and for cancer.

show abstract

Antigen-Specific CD8 T Cells Can Eliminate Antigen-Bearing Keratinocytes with Clonogenic Potential via an IFN-γ-Dependent Mechanism

Cited by 3 publications

References 41 publications

The Kinematics of Cytotoxic Lymphocytes Influence Their Ability to Kill Target Cells

The Kinematics of Cytotoxic Lymphocytes Influence Their Ability to Kill Target Cells

IL-17 Suppresses Immune Effector Functions in Human Papillomavirus-Associated Epithelial Hyperplasia

Interferon-γ derived from cytotoxic lymphocytes directly enhances their motility and cytotoxicity

Contact Info

Product

Resources

About