'Relaxed' T cells critical to immune response
Researchers model how cells handle invaders, ignore imposters

Date:
June 16, 2020
Source:
Rice University
Summary:
Researchers model the role of relaxation time as T cells bind
to invaders or imposters, and how their ability to differentiate
between the two triggers the body's immune system.



FULL STORY ==========================================================================
Like finding that needle in the haystack every time, your T cells manage
what seems like an improbable task: quickly finding a few invaders among
the many imposters in your body to trigger its immune response.


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T cells have to react fast and do so nearly perfectly to protect people
from diseases. But first, they need a little "me" time.

Rice University researchers suggest that has to do with how T cells
"relax" in the process of binding to ligands -- short, functional
molecules -- that are either attached to the invaders or just resemble
them.

The look-alikes greatly outnumber the antigen ligands attached to
attacking pathogens. The theory by Rice chemist Anatoly Kolomeisky and
research scientist and Rice alumnus Hamid Teimouri proposes that the T
cell's relaxation time - - how long it takes to stabilize binding with
either the invader or the imposter -- is key. They suggested it helps
explain the rest of the cascading sequence by which invaders prompt the
immune system to act.

The inappropriate activation of a T cell toward its own molecules leads
to serious allergic and autoimmune responses.

The researchers' study appears in the Biophysical Journal.



==========================================================================
T cells operate best within the parameters that control a "golden
triangle" of sensitivity, specificity and speed. The need for speed seems obvious: Don't let the invaders infect. And it is important because T
cells spend so little time in the vicinity of the antigen-presenting
cells, so they must act quickly to recognize them. Specificity is most challenging, since self-ligand imposters can outnumber invaders by a
factor of 100,000.

"It is amazing how T cells are able to react so fast and so
selectively. This is one of the most important secrets of living
organisms," said Kolomeisky, a professor and chairman of Rice's Department
of Chemistry and a professor of chemical and biomolecular engineering.

Their approach was to build a stochastic (random) model that analyzed how
T cell receptors bind step-by-step to the peptide major histocompatibility complexes (pMHC) on the surface of antigen-presenting cells. At a high
enough concentration, the bound complexes trigger the immune cascade.

The mathematical model aligned with experimental results that suggest T
cell activation depends on kinetic proofreading, a form of biochemical
error correction. Proofreading slows down the relaxation for wrong
molecules, and this allows the organism to start the correct immune
response.

While the theory helps explain the T cells' "absolute discrimination,"
it does not explain downstream biochemical processes. However, the
researchers said timing may have everything to do with those as well.

In a "very speculative" suggestion, the researchers noted that when the
binding speed of imposters matches that of invaders, triggering both biomolecular cascades, there's no immune response. When the more relaxed binding of pathogenic ligands lags behind, it appears more likely to
reach a threshold that triggers the immune system. Kolomeisky said the
concept could be validated through experimentation.

He and Teimouri wrote that many other aspects of T cell triggering need to
be explored, including the roles of the cellular membranes where receptors
are located, cell-cell communications, and cell topography during
interactions. But having a simple quantitative model is a good start.

"Our theory can be extended to explore some important features of the
T cell activation process," Kolomeisky said.


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


========================================================================== Journal Reference:
1. Hamid Teimouri, Anatoly B. Kolomeisky. Relaxation times of ligand-
receptor complex formation control T cell activation. Biophysical
Journal, 2020; DOI: 10.1016/j.bpj.2020.06.002 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200616135744.htm

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