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Imaging the Human Immunological Synapse
Published on: December 26, 2019
16.0K
Failed CTL/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time
Misty R Jenkins1, Jesse A Rudd-Schmidt2, Jamie A Lopez2
1Cancer Cell Death and Killer Cell Biology Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia The Sir Peter MacCallum Department of Oncology; Department of Genetics; and Department of Medicine, St. Vincent's Hospital; The University of Melbourne, Parkville, Victoria 3010, Australia misty.jenkins@petermac.org joe.trapani@petermac.org.
The Journal of Experimental Medicine
|March 4, 2015
Summary
Failed cytotoxic T lymphocyte (CTL) and natural killer (NK) cell killing of target cells amplifies inflammatory cytokine release. Target cell death signals normally trigger lymphocyte detachment, preventing cytokine storms.
Area of Science:
- Immunology
- Cellular Biology
- Molecular Medicine
Background:
- Failure of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells to induce target cell apoptosis via perforin/granzyme pathways leads to immune dysregulation.
- Familial hemophagocytic lymphohistiocytosis (FHL) involves a
- cytokine storm
- linked to macrophage overactivation, but the connection to failed target cell death remains unclear.
Purpose of the Study:
- To elucidate the cellular mechanism linking failed lymphocyte-mediated cytotoxicity to systemic inflammation.
- To investigate how prolonged target cell survival impacts cytokine secretion and lymphocyte behavior.
- To identify the signals that regulate lymphocyte disengagement from target cells.
Main Methods:
- Live cell microscopy to observe interactions between CTLs/NK cells and target cells in real-time.
- Analysis of cytokine secretion profiles (IL-2, TNF, IFN-γ, chemokines) from lymphocytes and macrophages.
- Pharmacological blockade of caspases to assess the role of target cell death in lymphocyte disengagement.
Main Results:
- Prolonged target cell survival significantly amplifies inflammatory cytokine production by CTLs/NK cells.
- Interferon-gamma (IFN-γ) from lymphocytes activates naive macrophages, leading to secondary IL-6 overproduction.
- Failed lymphocyte disengagement from targets, indicated by increased synapse time, correlates with cytokine hypersecretion.
- Target cell-derived, caspase-dependent signals are crucial for lymphocyte detachment; caspase inhibition prevents disengagement and causes cytokine hypersecretion.
Conclusions:
- Failed lymphocyte killing of target cells leads to amplified cytokine release and systemic inflammation.
- Target cell death, mediated by caspases, provides essential signals for lymphocyte disengagement.
- Understanding these mechanisms offers insights into immune dysregulation in conditions like FHL and informs therapeutic strategies.
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