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SUNDAY SCIENCE: IMMUNE CELLS CAN ADAPT TO INVADING PATHOGENS,
DECIDING WHETHER TO FIGHT NOW OR PREPARE FOR THE NEXT BATTLE  
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Kathleen Abadie, Elisa Clark, Hao Yuan Kueh
March 8, 2024
The Conversation
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_ How does your immune system decide between fighting invading
pathogens now or preparing to fight them in the future? Turns out, it
can change its mind. _

Understanding the flexibility of T cell memory can lead to improved
vaccines and immunotherapies., Juan Gaertner/Science Photo Library via
Getty Images

 

Kathleen Abadie
[[link removed]],
_University of Washington
[[link removed]]_;
Elisa Clark
[[link removed]],
_University of Washington
[[link removed]]_,
and Hao Yuan Kueh
[[link removed]],
_University of Washington
[[link removed]]_

_Disclosure statement_

_Kathleen Abadie was funded by a NSF (National Science Foundation)
Graduate Research Fellowships. She performed this research in
affiliation with the University of Washington Department of
Bioengineering._

_Elisa Clark performed her research in affiliation with the University
of Washington (UW) Department of Bioengineering and was funded by a
National Science Foundation Graduate Research Fellowship (NSF-GRFP)
and by a predoctoral fellowship through the UW Institute for Stem Cell
and Regenerative Medicine (ISCRM)._

_Hao Yuan Kueh receives funding from the National Institutes of
Health._

How does your immune system decide between fighting invading pathogens
now or preparing to fight them in the future? Turns out, it can change
its mind [[link removed]].

Every person has 10 million to 100 million unique T cells
[[link removed]] that have a critical job in
the immune system: patrolling the body for invading pathogens or
cancerous cells to eliminate. Each of these T cells has a unique
receptor that allows it to recognize foreign proteins on the surface
of infected or cancerous cells. When the right T cell encounters the
right protein, it rapidly forms many copies of itself to destroy the
offending pathogen.

Importantly, this process of proliferation gives rise to both
short-lived effector T cells that shut down the immediate pathogen
attack and long-lived memory T cells that provide protection against
future attacks. But how do T cells decide whether to form cells that
kill pathogens now or protect against future infections?

[Diagram of cytotoxic T cell killing a target cell]
[[link removed]]

Cytotoxic T cells bind to foreign proteins on infected or cancerous
cells and subsequently destroy those target cells by releasing
molecules like granzyme and perforin. Anatomy & Physiology/SBCCOE
[[link removed]],
CC BY-NC-SA [[link removed]]

We are
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a team
[[link removed]]
of bioengineers
[[link removed]]
studying how immune cells mature. In our recently published research
[[link removed]], we found that having
multiple pathways to decide whether to kill pathogens now or prepare
for future invaders boosts the immune system’s ability to
effectively respond to different types of challenges.

Fight or remember?

To understand when and how T cells decide to become effector cells
that kill pathogens or memory cells that prepare for future
infections, we took movies of T cells dividing
[[link removed]] in response to a
stimulus mimicking an encounter with a pathogen.

Specifically, we tracked the activity of a gene called T cell factor
1, or TCF1. This gene is essential for the longevity of memory cells.
We found that stochastic, or probabilistic, silencing of the TCF1 gene
when cells confront invading pathogens and inflammation drives an
early decision [[link removed]] between
whether T cells become effector or memory cells. Exposure to higher
levels of pathogens or inflammation increases the probability of
forming effector cells.

Surprisingly, though, we found that some effector cells that had
turned off TCF1 early on were able to turn it back on
[[link removed]] after clearing the
pathogen, later becoming memory cells.

Through mathematical modeling, we determined that this flexibility in
decision making among memory T cells is critical to generating the
right number of cells that respond immediately and cells that prepare
for the future, appropriate to the severity of the infection.

Understanding immune memory

The proper formation of persistent, long-lived T cell memory is
critical to a person’s ability to fend off diseases ranging from the
common cold to COVID-19 to cancer.

From a social and cognitive science perspective
[[link removed](93)E0210-O], flexibility allows
people to adapt and respond optimally to uncertain and dynamic
environments. Similarly, for immune cells responding to a pathogen,
flexibility in decision making around whether to become memory cells
may enable greater responsiveness to an evolving immune challenge.

Memory cells can be subclassified into different types
[[link removed]] with distinct features
and roles in protective immunity. It’s possible that the pathway
where memory cells diverge from effector cells early on and the
pathway where memory cells form from effector cells later on give rise
to particular subtypes of memory cells.

Our study focuses on T cell memory in the context of acute infections
the immune system can successfully clear in days, such as cold, the
flu or food poisoning. In contrast, chronic conditions such as HIV and
cancer require persistent immune responses; long-lived, memory-like
cells are critical for this persistence. Our team is investigating
whether flexible memory decision making also applies to chronic
conditions and whether we can leverage that flexibility to improve
cancer immunotherapy.

Resolving uncertainty surrounding how and when memory cells form could
help improve vaccine design and therapies that boost the immune
system’s ability to provide long-term protection against diverse
infectious diseases.

_This article was updated to replace a figure of T cell
differentiation with cytotoxic T cell activity._[The Conversation]

Kathleen Abadie
[[link removed]], Ph.D.
Candidate in Bioengineering, _University of Washington
[[link removed]]_;
Elisa Clark
[[link removed]], Ph.D.
Candidate in Bioengineering, _University of Washington
[[link removed]]_,
and Hao Yuan Kueh
[[link removed]],
Associate Professor of Bioengineering, _University of Washington
[[link removed]]_

This article is republished from The Conversation
[[link removed]] under a Creative Commons license. Read
the original article
[[link removed]].

Cellular Self-Destruction May Be Ancient. But Why?
[[link removed]]
Veronique Greenwood
Quanta Magazine
How did cells evolve a process to end their own lives? Recent research
suggests that apoptosis, a form of programmed cell death, first arose
billions of years ago in bacteria with a primitive sociality.
March 6, 2024

* Science
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* biology
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* immune system
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* infectious diseases
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