Could releasing `handbrake' immune cells help supercharge immunity?


Date:
April 14, 2022
Source:
Walter and Eliza Hall Institute
Summary:
Researchers have found a way to supercharge immune cells that
could enable them to clear disease and infections faster


FULL STORY ==========================================================================
T cells are immune cells that help our bodies fight disease by seeking
and destroying unhealthy cells.


========================================================================== Regulatory T cells, or Treg cells, put the brakes on T cells, preventing
them from misbehaving and attacking the body's healthy tissues.

Researchers have now discovered a way to release the "handbrake" hold
that Treg cells have over normal T cells and intentionally put them
into overdrive.

Lifting this restraint could supercharge the response of T cells and lead
to better treatment options for cancers and infections, where patients
would benefit from rapid clearance of the unhealthy cells.

The research, led by Dr Charis Teh, Simon Preston, Associate Professor
Daniel Gray and Professor Marc Pellegrini, is published in Science
Immunology.

At a glance
* Researchers have found a way to supercharge T cell responses,
which could
be used to clear some infections and cancers faster.

* By taking the regulatory "handbrake" off, the T cells were able
to go
into overdrive and boost the immune response.

* The findings offer a better understanding of how T cells can be
manipulated to fight diseases like cancer and infections, while
avoiding the risk of autoimmune conditions like diabetes and
multiple sclerosis.

Boosted response


==========================================================================
The team blocked the activity of an enzyme in Treg cells to assess its
role in the immune response.

They found the enzyme, known as caspase-8, controlled the survival of
Treg cells in a manner that depended on the immune environment.

Restraining the enzyme in healthy settings enabled Treg cells to survive
and accumulate. But when they blocked caspase-8 in Treg cells during an infection, this triggered a form of cell death called necroptosis.

Associate Professor Daniel Gray said inhibiting caspase-8 in Treg cells
is a critical step that releases their restraint of T cells.

"Releasing this "handbrake" would greatly assist patients fighting
certain debilitating conditions, such as chronic infections, as the T
cells are then able to work overtime to drive the infection down or away.



==========================================================================
"But there is risk when too many Treg cells die, as this can lead to
autoimmune conditions like diabetes and multiple sclerosis.

"Knowing where the immune response can be supercharged to a level that
will boost immunity, but not cause autoimmune disease, will be integral
to advancing new immunotherapies in the future. Our research findings
bring the scientific field closer to establishing this threshold."
A therapeutic window By testing a clinically approved drug on human
Treg cells, the researchers found they died more readily than normal T
cells. This discovery identified a "therapeutic window" where Treg cells
could be targeted for death while sparing normal T cells.

"If we were to target caspase-8 in Treg cells correctly, we could
temporarily reduce their suppression on the immune system to enable
better defence against certain infections and cancers," Dr Teh said.

"Our findings have revealed a new role for this enzyme that could be
exploited to fine tune the balance of the immune response to pathogens,
cancer and healthy, normal cells."

========================================================================== Story Source: Materials provided by Walter_and_Eliza_Hall_Institute. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Charis E. Teh, Simon P. Preston, Alissa K. Robbins, Michael
D. Stutz,
James Cooney, Michelle P. Clark, Antonia N. Policheni, Cody
C. Allison, Liana Mackiewicz, Philip Arandjelovic, Gregor Ebert,
Marcel Doerflinger, Tania Tan, Lucille C. Rankin, Peggy P. Teh,
Gabrielle T. Belz, Axel Kallies, Andreas Strasser, Marc Pellegrini,
Daniel H. D. Gray. Caspase- 8 has dual roles in regulatory T
cell homeostasis balancing immunity to infection and collateral
inflammatory damage. Science Immunology, 2022; 7 (69) DOI:
10.1126/sciimmunol.abn8041 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220414110850.htm

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