The BCell Coreceptor Complex Can Enhance BCell Responses

Stimulation through antigen receptors can be modified significantly by signals through coreceptors. Recall that co-stimulation through CD28 is an essential feature of effective positive stimulation of T lymphocytes, while signaling through CTLA-4 inhibits the response of the T cell. In B cells

VISUALIZING CONCEPTS

Antigen

VISUALIZING CONCEPTS

Antigen

Small G-protein pathways

PCK-mediated pathways

Ca2+-mediated pathways

Small G-protein pathways

PCK-mediated pathways

Ca2+-mediated pathways r

Changes in pattern of gene expression

> Functional changes in cells Differentiation

> Activation

FIGURE 11-8

Some of the many signal-transduction pathways activated by the BCR. In one pathway, Syk activates PLC72 by tyrosine phosphorylation. PLC72 then hydrolyzes PIP2, a membrane phospholipid, to produce the second messengers DAG and IP3. DAG and Ca2+ released by the action of IP3 collaboratively activate the PKC, which induces additional signal-transduction pathways. The activated receptor complex also generates signals that activate the Ras pathway. Activated Ras initiates a cascade of phosphorylations that culminates in the activation of transcription factors that up-regulate the expression of many genes.

a component of the B-cell membrane, called the B-cell core-ceptor, provides stimulatory modifying signals.

The B-cell coreceptor is a complex of three proteins: CD19, CR2 (CD21), and TAPA-1 (CD81) (Figure 11-9). CD 19, a member of the immunoglobulin superfamily, has a long cyto-plasmic tail and three extracellular domains. The CR2 component is a receptor of C3d, a breakdown product of the complement system, which is an important effector mechanism for destroying invaders (Chapter 13); note that the involvement of C3d in the pathway for coreceptor activity reveals different arms of the immune system interacting with each other. CR2 also functions as a receptor for a membrane molecule and the transmembrane protein TAPA-1. In addition to the stimulatory coreceptor, another molecule, CD22, which is constitutively associated with the B-cell receptor in resting B cells, delivers a negative signal that makes B-cells more difficult to activate. As shown in Figure 11-9, the CR2 component of the coreceptor complex binds to complement-coated antigen that has been captured by the mIg on the B cell. This crosslinks the coreceptor to the BCR and allows the CD19 component of the coreceptor to interact with the Ig-a/Ig- p component of the BCR. CD19 contains six tyrosine residues in its long cytoplas-mic tail and is a major substrate of the protein tyrosine kinase activity that is mediated by crosslinkage of the BCR. Phospho-rylation of CD19 permits it to bind a number of signaling molecules, including the protein tyrosine kinase Lyn.

The delivery of these signaling molecules to the BCR complex contributes to the activation process, and the coreceptor

CLINICAL FOCUS

CLINICAL FOCUS

X-Linked Agammaglobulinemia: A Failure in Signal Transduction and B-Cell Development

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