A small switch with a big impact

Date:
October 5, 2020
Source:
University of Wu"rzburg
Summary:
Minor changes in immune cells can significantly affect the immune
response, scientists have now discovered. Their findings could be
relevant for stem cell therapy.



FULL STORY ==========================================================================
T cells play a key role in the human immune system. They are capable
of distinguishing diseased or foreign tissue from the body's own,
healthy tissue with great accuracy; they are capable of triggering the
actions necessary to fight off the troublemakers. The details of this
immune response are manifold and the individual steps are not yet fully understood.


========================================================================== Scientists of the universities of Wu"rzburg and Mainz have now figured
out new details of these processes, showing that tiny point mutations in a
gene can modify T cells to be less aggressive. This could be an advantage
after stem cell transplantation which includes T-cell transfusion in order
to keep a number of severe side effects in check. The researchers have
now published the results of their study in the Journal of Experimental Medicine. The study is led by Dr Friederike Berberich-Siebelt, head of
the "Molecular and cellular immunology" research group at the Institute
of Pathology of the University of Wu"rzburg.

A protein family with multiple tasks When T cells detect foreign or
altered tissue, such as an infected or tumour tissue, this usually happens through the receptors on their cell surface. These T-cell receptors
then send signals into the cell interior, initiating a response. In a
first step, they activate a special family of transcription factors -- scientifically called NFAT for nuclear factor of activated T-cells.

The NFATs then bind to the DNA in the cell nucleus and trigger also the production of cytokines such as interleukin-2.

NFAT is composed of many family members which may have overlapping
tasks or assume completely different functions. But that's not all:
Like many other proteins in the cell, they can still be modified after
their synthesis to customize their function. The recently published
study focuses on one specific modification of the NFATc1 "family member"
which is called sumoylation.

Advantageous point mutations "Sumoylation plays a role in different
cellular processes such as nuclear transport, programmed cell
death or as an antiviral mechanism," Friederike Berberich-Siebelt
explains. Sumoylation defects have also been observed in various diseases
such as cancer and herpesvirus infections.

In the study now published, the scientists worked with laboratory
animals that had two actually insignificant point mutations in
the NFATc1 gene which, however, prevent sumoylation. This is not
necessarily a disadvantage: "The offspring of these animals is perfectly healthy. The modified NFATc1 even mediates specific signals that reduce
the clinical symptoms of multiple sclerosis at least in the animal model," Berberich-Siebelt explains. When using T cells that carry these mutations
in stem cell transplantation, they are much less aggressive against the
tissues of the host animals than "normal" cells.

Fascinating fundamental research This effect is due to an increase in interleukin-2 at the beginning of the immune response at the biomolecular level. Interleukin-2 counteracts the differentiation into inflammatory
T-cell subtypes and at the same time supports so-called regulatory T cells according to the authors of the study. It is quite possible that this
discovery will have consequences for future stem cell transplantation
which includes T-cell infusion. When using T cells in which NFATc1 is
not sumoylated, this might prevent severe side effects, making the point mutation "a small modification with a big impact" according to Berberich- Siebelt.

To investigate this in more detail, Berberich-Siebelt and her team will continue to research the possibilities of therapeutic implementation
within the framework of the Collaborative Research Center/Transregio
"Control of graft- versus-host and graft-versus-leukaemia immune responses after allogeneic stem cell transplantation" funded by the German
Research Foundation (DFG). "We want to find out whether CRISPR/Cas9
gene editing can be applied to human T cells to exhibit just the right
amount of activity during hematopoietic stem cell transplantation,"
the scientist says.

But the new findings are also relevant independently of these potential consequences for therapeutic applications. "We are basically interested
in understanding the fine regulation in cells, such as the T-cell
receptor signalling and the function of NFAT family members and their
isoforms in this context," says Berberich-Siebelt who finds the newly
published results "fascinating." After all, the scientists did not have
to switch off a gene or activate it excessively as is often the case in research. Instead, two actually harmless point mutations and subtle direct effects were sufficient to ultimately flip the switch from inflammation, autoimmunity and rejection to tolerance. A small shift of the focus at the beginning of the immune response had been sufficient to accomplish this.


========================================================================== Story Source: Materials provided by University_of_Wu"rzburg. Original
written by Gunnar Bartsch. Note: Content may be edited for style and
length.


========================================================================== Journal Reference:
1. Yin Xiao, Musga Qureischi, Lena Dietz, Martin Vaeth, Subrahmanya D.

Vallabhapurapu, Stefan Klein-Hessling, Matthias Klein, Chunguang
Liang, Anika Ko"nig, Edgar Serfling, Anja Mottok, Tobias Bopp,
Andreas Rosenwald, Mathias Buttmann, Ingolf Berberich, Andreas
Beilhack, Friederike Berberich-Siebelt. Lack of NFATc1 SUMOylation
prevents autoimmunity and alloreactivity. Journal of Experimental
Medicine, 2021; 218 (1) DOI: 10.1084/jem.20181853 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201005101534.htm

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