B-Cell Co-Receptors and Lymphocyte Activation

• Lymphocyte activation can be significantly altered through signals from co-receptors.
• B-cell receptor co-receptors are critical for effective and positive B-cell stimulation.
• CD19, CD21, and CD81 collectively form the B-cell co-receptor complex, which provides a critical second signal to B cells.
• CD22 deactivates B cells and is important for negative regulation.

B Cell Co-Receptor Components

• CD21, also known as CR2, acts as a receptor for C3d, a breakdown product of the complement system used in opsonizing pathogens.
• CD21 binds to antigens coated with C3d, which causes cross-linking on the B-cell surface.
• Crosslinking via C3d brings CD81 and CD19 closer to the Ig-alpha and Ig-beta portions of the BCR.
• CD19 gets phosphorylated after the binding of several signaling molecules located in its cytoplasmic tail.

ITAMs and ITIMs

• B and T cell antigen receptors share motifs that link antigen receptors to intracellular signaling cascades.
• These motifs, ITAMs and ITIMs, regulate the quality and magnitude of immune responses and provide immunological controls.
• ITAM stands for immunoreceptor tyrosine-based activation motifs
• ITIM stands for immunoreceptor tyrosine-based inhibitory motifs

Functional Role of ITIMs and ITAMs

• Activation of Syk and Zap70 occurs after binding to the dually phosphorylated ITAM, which leads to recruitment and phosphorylation of multiple signaling molecules.
• Co-ligation of ITAM-containing receptors with ITIM-containing co-receptors can reduce or eliminate a cellular response.
• Substrate SHP1 initiates inhibitory signals by decreasing calcium and phosphorylation of ITAMs.
• SHP1 directly removes phosphate groups from substrate groups, reverting the signaling cascade to the earliest events.

B Cell Receptor Complex

• The B cell surface includes membrane-bound IgM (the B cell receptor), as well as co-receptors like CD21, CD19, and CD81.
• Ig-alpha and Ig-beta are important components in B cell receptor signaling.
• Under normal conditions (low pathogen invasion), B cell receptors are separated and uniformly distributed in the cell membrane.
• Upon encountering a pathogen, B cell receptors cluster in lipid rafts of specific sub-domains on the B cell surface.
• Receptor clustering is an important event
• Kinases, like Lyn kinase, can be part of the lipid raft and can phosphorylate components of the B cell receptor cluster.
• Ig-alpha and Ig-beta are molecules of the IG superfamily containing immunoreceptor tyrosine kinase-based activation motifs (ITAMs).
• ITAMs are phosphorylation sites for SRC family kinases, such as Lyn kinase.
• Phosphorylated ITAMs are docking sites for adapter molecules like SLP.
• The SLP adapter serves as a platform for the binding of several signaling components, which allows for MAP kinase signaling to be triggered.

Review Questions

• B cell activation is initiated by clustering or crosslinking of the BCR, which leads to the phosphorylation of Igα and Igβ
• The BCR equivalent of ZAP-70 in TCR mediated signaling, which is responsible for initiating the signaling cascade is Syk.