How T cells kill cancer cells at the cytotoxic immune synapse

How T cells kill cancer cells
How T cells kill cancer

A report published in The Journal of Immunology identifies how T cells kill cancer cells, i.e., the spatiotemporal events, the role of calcium flux and the degranulation of cytotoxic lymphocytes in the process of rapid formation by these cells of immune synapses and the killing of their target cells.

T cell dependent immune responses protect the host from cancer but also participate in destructive autoimmunity. If these interactions are dysregulated, the host is susceptible to pathogens or tumor escape at one extreme and autoimmunity at the other.

Cytotoxic lymphocytes (CLs) identify pathogen-infected and transformed target cells and eliminate them primarily through granule-mediated apoptosis. The cytotoxic lymphocytes destroy virus-infected and malignant cells via an effective engagement with their target cells and a process entitled ‘immunological synapse’.

The ‘immune synapses’ are crucial factor for the killing of virus-infected or malignant cells. Immune synapses’ formation triggers exocytosis of lytic granules containing the effector molecules perforin and granzymes, into the synaptic cleft, in a process known as degranulation. Of note, perforin forms transmembrane pores in the target cell, allowing direct diffusion of extracellular milieu, including granzymes into the target cell cytosol, where they activate apoptosis pathways.

Regulated Ca2+ flux following receptor activation is essential for CL degranulation and target cell killing and represents an early CL signaling event, but it is unclear how Ca2+ signaling dictates degranulation events in the CLs.

In some cases, the nano-scale gap of the immunological synapse take place between T cells and antigen presenting cells, and this bears a striking similarity to the classical synapse of the central or peripheral nervous system.

The immunological synapse or kinapse integrates three broad categories of receptors: antigen (TCR), adhesion, and costimulatory/checkpoint. Adhesion molecules provide the energy needed to pull cells together, allowing sustained antigen recognition and precise execution of effector functions. Whereas, co-stimulatory and checkpoint receptors alter the functional outcome of immunological synapse formation substantially and can also influence the synapse-kinapse balance.

Many of the processes governing effector function are conserved between CTLs and Natural Killer (NK) cells, but NK cells show weak calcium influxes, whereas CTLs show high, sustained calcium influxes. Previously it has not been technically possible to investigate the dynamics of NK- and CTL-target cell engagement in detail.

In the Journal of Immunology study the researchers from East Melbourne, Victoria, Australia have used a novel live cell microscopy technique to visualize the engagement of primary human and mouse T cytotoxic lymphocytes with their targets and the subsequent delivery of the lethal hit.

”For the first time we have got this marker of the delivery of the lethal hit” said immunologist Misty Jenkins from the Peter MacCallum Cancer Centre.

Using this technique, the researchers have uncovered two critical features of the lethal hit: a defined focal delivery and rapid target cell membrane resealing.

As discussed by the authors of the Journal of Immunology study, the efficiency of CL serial killing is determined by the ability of CLs to rapidly form functional immune synapses with specific cell targets. Thus, this study defines the spatiotemporal properties governing engagement of CLs with their target and delivery of the lethal hit and further demonstrates the unidirectionality of perforin pore formation at the IS.

The study suggests, and as Bridie Smith described this phenomenon – it takes no more than 100 seconds for the body’s immune cells to identify and kill a cancer cell. And for the first time, researchers have gained an insight into how the body’s immune system, and particularly T-cells, react to diseased or virus-infected cells.

This is perhaps the first study showing that perforin pore delivery is unidirectional, occurring exclusively on the target cell membrane, but sparing the killer cell, thus offering new insight into how CLs protect themselves during attack of a target. The study demonstrates for the first time that CL protection is due to an inability of perforin to form transmembrane pores on the presynaptic CL membrane during delivery of the lethal hit.

Source: J Immunol. 2013 Sep 1;191(5):2328-34. doi: 10.4049/jimmunol.1301205. Epub 2013 Jul 24.
Read more: The Journal of Immunology
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