Two-faced protein both inhibits and activates B cell receptor signaling


Date:
April 4, 2022
Source:
Tokyo Medical and Dental University
Summary:
Researchers have found that restoration of B cell function in BCR
signaling deficiencies involves the interaction of CD22, normally
an inhibitory factor, with binding partners on the same cell,
which results in upregulation of BCR expression and paradoxically
increased BCR signaling. These findings suggest that CD22 could be
a novel target for the treatment of patients with B cell signaling
deficiencies such as X- linked agammaglobulinemia.



FULL STORY ==========================================================================
The rules to the kids' game "red light, green light" are easy to follow:
red always means stop, and green always means go. But now, researchers
from Japan have found that a key protein involved in B cell signaling
acts as both a red light to signaling in healthy cells and a green light
to signaling in immune- deficient cells.


==========================================================================
In a study published in March in Science Signaling, researchers from
Tokyo Medical and Dental University (TMDU) have revealed that CD22, a
crucial molecule in B cell signaling, switches from an inhibitory role
to an activating role when B cell receptor (BCR) signaling is compromised
due to a genetic defect that causes an immune disorder.

Contact between BCRs and foreign invaders prompts B cells to make
antibodies, and CD22 inhibits BCR signaling to keep B cells from inappropriately releasing antibodies. Interestingly, previous research
suggests that this inhibition is regulated by binding of CD22 to other
factors expressed on the same cell. In contrast, a protein called CD45
is a main activator of BCR signaling, and defects in the gene encoding
CD45 cause an immunodeficiency syndrome.

"CD45 normally enhances BCR signaling," explains Chizuru Akatsu, lead
author on the study. "When CD45 is missing in laboratory cell lines, BCR signaling is dramatically decreased; however, signaling is not affected as severely in mice when CD45 is missing, which suggests that there is some
kind of compensatory mechanism at work." To investigate the relationship between CD22 and BCR signaling restoration in the absence of CD45, the researchers disrupted the binding of all interaction partners of CD22
either continuously or for a short time and looked at the effect this
had on BCR signaling.

"The results were entirely unexpected," says Takeshi Tsubata, senior
author.

"Acute disruption of binding between CD22 and its ligands did not affect
the restoration of BCR signaling in B cells lacking CD45, whereas
continuous disruption of this binding resulted in markedly less BCR
signaling recovery." As it turns out, the cells in which signaling was restored expressed unusually high levels of BCR, which accounted for their ability to continue functioning relatively normally. BCR signaling occurs
at low levels even in the absence of stimulation by foreign antigens, and
this low-level steady-state signaling is required for B cell development
and survival. Because BCR is an endogenous ligand of CD22, continuous
CD22 binding to its ligands facilitates inhibition of steady-state BCR signaling by CD22. If BCR signaling is compromised by a defect such
as CD45 deficiency, steady-state signaling is markedly reduced by the
signaling defect together with the signal inhibition by CD22; therefore,
only B cells that express high levels of BCR survive. Through this
mechanism, CD22 paradoxically restores BCR signaling in immune-deficient
B cells.

"What is really interesting about this result is that it could point
toward a way to restore immune function in patients with immune disorders involving B cell signaling deficiencies," states Akatsu.

Given that B cells and immunoglobulins are present -- though in greatly
reduced numbers -- in immunodeficient patients with defects in BCR
signaling, CD22 may be a useful treatment target. Activating CD22
could help restore B cell function in patients with B cell signaling deficiencies such as X-linked agammaglobulinemia.


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


========================================================================== Journal Reference:
1. Chizuru Akatsu, Amin Alborzian Deh Sheikh, Naoko Matsubara, Hiromu
Takematsu, Astrid Schweizer, Hajjaj H. M. Abdu-Allah, Thomas
F. Tedder, Lars Nitschke, Hideharu Ishida, Takeshi Tsubata. The
inhibitory coreceptor CD22 restores B cell signaling by
developmentally regulating Cd45 -/- immunodeficient B cells. Science
Signaling, 2022; 15 (723) DOI: 10.1126/scisignal.abf9570 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220404120445.htm

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