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Printable Handouts
Navigable Slide Index
- Introduction
- Cytotoxic T Lymphocytes (CTL) kill virally infected cells and cancer cells
- Lecture aim
- A (very) short history of CTLs
- How do CTLs begin?
- The microenvironment is important
- The type of cytokine in the microenvironment shapes T cell development
- What do cytotoxic T cells look like?
- Immunological synapses
- Cytolytic granules are specialised “secretory lysosomes”
- The microenvironment is important: Hypoxia
- Perforin and Fas ligand both contribute to rapid killing
- Other killer cells and their receptors
- CTLs are very effective killers
- Granules move along microtubules to the centrosome
- Pioneer microtubules pull the centrosome to the synapse
- Gene disruption in mice
- A key paper in understanding perforin function
- Familial Haemophagocytic Lymphohistiocytosis (FHL)
- FHL pathway
- FHL patients without perforin gene mutations
- OtOther mutations giving rise to HLH or FHL were identified
- Other FHL mutations disrupted different stages of granule secretion
- CTL killing needs to be finely controlled
- Controlling CTL killing
- How do CTL fine-tune their killing?
- An actin barrier controls secretion across the synapse
- Rapid actin depletion as a synapse forms with the target
- Secretion is terminated by rapid actin recovery
- How is actin depletion controlled across the synapse?
- TCR signaling triggers PIP2 conversion to DAG
- Spinning disk imaging captures rapid changes in 4D
- How TCR signaling controls actin depletion and secretion
- How can CTL killing be harnessed to treat cancer?
- Controlling the TCR using co-stimulatory signals
- Using chimeric antigen receptors to beat cancer: CAR-T cells
- Evolution of chimeric antigen receptors
- Antibodies against inhibitory receptors can allow CTLs to kill
- Anti-PD-1 acts at many different points
- Summary
- Thank you!
Topics Covered
- Cytotoxic T Lymphocytes (CTLs)
- Mechanism of action of CTLs
- CTL and the microenvironment
- Cytolytic granules
- Perforin and Fas ligand
- The role of pioneer microtubules
- Familial Haemophagocytic Lymphohistiocytosis (FHL)
- Controlling CTL killing
- The role of actin and actin depletion
- CTLs are being harnessed in immunotherapies
- Co-stimulatory signals and TCRs
- CAR-T cells
Links
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Therapeutic Areas:
External Links
Talk Citation
Griffiths, G.M. (2021, July 28). Cytotoxic T lymphocytes [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved December 21, 2024, from https://doi.org/10.69645/VZWJ3294.Export Citation (RIS)
Publication History
Financial Disclosures
- Prof. Gillian M. Griffiths has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
Other Talks in the Series: The Immune System - Key Concepts and Questions
Transcript
Please wait while the transcript is being prepared...
0:00
Hello, I'm Gillian Griffiths and I'm the Professor of
Immunology and Cell Biology at the University of Cambridge in the UK.
I'm going to give a talk today about cytotoxic T lymphocytes.
0:12
Cytotoxic T lymphocytes are
incredibly important cells for the immune system, because they kill
virally infected and cancerous cells, and they do so remarkably effectively.
You can see that in this little video here, where
the cytotoxic T lymphocyte is labelled with
its actin cytoskeleton in orange, and we can see it
as it attacks the cancerous cell, where the membrane has been marked with a blue marker.
They are very good and very effective, and this
has had very important medical consequences recently.
0:45
New therapies that have harnessed the power of
these cytotoxic T-cells have led to remarkable breakthroughs in cancer treatments.
What I would like to try and outline in this lecture, is how much we know about
how cytotoxic T lymphocytes work, and
explain to you how this is being harnessed in immunotherapies.
1:06
If I were to give a very short history of cytotoxic T lymphocytes,
I would outline advances that were made in each of these decades.
In the 1950s, cytotoxic T lymphocytes were initially
investigated to understand graft rejection, and it wasn't until
the 1960s that it was realised that these were sensitised
lymphoid cells that could be found to lyse target cells.
In the 1970s it was found to be T-cells that
were responsible for cytotoxicity, and in fact,
there were some remarkable videos which showed these little cells
as serial killers, destroying one target after another.
This moved into a molecular age in the 1980s, where
the cytolytic proteins were identified, and they were all
found to be packaged in little granules that could be
released when the cytotoxic T lymphocyte met its target.
The key proteins in this process were found to be perforin
(which was initially called 'cytolysin'), and a series of granzymes,
which stood for 'granule-contained enzymes'.
Then in the 1990s, the therapeutic side of these came to the fore as CAR-T cells
(chimeric antigen-receptor T-cells)
were shown to be able to treat some blood cancers.
It's come on yet further, as I will explain, with checkpoint inhibitors in the following years.