# CD79A as a molecular switch regulating B cell activation

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $541,908

## Abstract

B lymphocytes are critical players in the development of protective immunity, as well as in pathological states
such as autoimmunity. Careful regulation of the strength and quality of biochemical signals that originate from
their antigen receptors (BCR) is essential to prevent the unwanted activation of potentially harmful autoreactive
B cells, and to generate optimally protective antibody responses. Inhibitory signaling mechanisms play a
central role in regulating BCR signaling. Best characterized is the role of Immunoreceptor Tyrosine-based
Inhibitory Motif (ITIM)-containing inhibitory receptors that become activated upon co-aggregation with actively
signaling BCRs. The BCR-associated Src-family kinase Lyn tyrosine phosphorylates their ITIM motifs, resulting
in the recruitment of phosphatases such as the tyrosine phosphatase SHP-1 and the inositol phosphatase
SHIP-1 that actively suppress BCR signaling. SHIP-1 activity is increased in autoreactive B cells and plays a
critical role in maintaining B cell tolerance by suppressing PI3K-dependent signaling. How SHIP-1 is activated
in autoreactive B cells is still unclear. BCR stimulation by itself, without recruitment of known ITIM-containing
inhibitory receptors, activates SHIP-1. In an unbiased screen, detecting tyrosine phosphorylated receptors that
bind SHIP-1, we identified CD79A as containing the SHIP-1 docking site. CD79A and CD79B form a
heterodimer that mediates signal transduction following BCR stimulation. Each chain contains a single
Immunoreceptor Tyrosine-based Activation Motif (ITAM). Phosphorylation of the two conserved tyrosines in the
ITAMs is the critical first step towards activating signaling. Previously, we showed that in autoreactive B cells
CD79A ITAMs are predominantly monophosphorylated. Studies of cell lines expressing chimeric receptors
suggest that monophosphorylation of the CD79A Y182 residue biases signaling towards inhibitory signaling.
We hypothesize that CD79A ITAMs can act like a molecular switch wherein ITAM monophosphorylation tips
the balance towards inhibitory signaling by preferentially recruiting the regulatory proteins Lyn and SHIP-1. To
test this hypothesis, we have generated novel mouse models in which the ability of the CD79A ITAM to
become tyrosine phosphorylated is variably restricted to monophosphorylation of the membrane proximal
(Y182) or membrane distal (Y193) residue. In Aim 1 we will determine how individual CD79A ITAM tyrosines
impact BCR signalosome composition and downstream signaling, both directly and indirectly via co-
aggregated ITIM-containing receptors. In Aim 2 we will determine the impact of individual CD79A ITAM
tyrosines on biological processes such as B cell development, B cell activation, antibody responses, and B cell
tolerance. Specifically, we will determine if CD79A ITAM monophosphorylation of CD79A Y182 drives the
anergic phenotype of autoreactive B cells. These studies will provide unique insights into the earliest activating
...

## Key facts

- **NIH application ID:** 10858586
- **Project number:** 1R01AI182423-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Andrew Getahun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $541,908
- **Award type:** 1
- **Project period:** 2024-08-12 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10858586

## Citation

> US National Institutes of Health, RePORTER application 10858586, CD79A as a molecular switch regulating B cell activation (1R01AI182423-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10858586. Licensed CC0.

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