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would have on the development of the secondary antibody response?

A. Lack of C3 means that immune complexes containing C3b and C3d do not form. Therefore they cannot bind to follicular dendritic cells (FDCs) via CR2 or engage with B cells via the B cell co-receptor complex (see Fig. 8.7); consequently B cell activation and the development of the secondary immune response is greatly impaired. (These experiments have been done by depleting mice of C3 using cobra venom factor.)

Direct interaction of B cells and T cells involves co-stimulatory molecules

Antigen-specific T cell populations can be obtained by growing and cloning T cells with antigens, APCs, and IL-2. It is therefore possible to visualize directly B cell and T cell clusters interacting in vitro:

• the T cells become polarized, with the TCRs concen- trated on the B cell side;

• the B cells also become polarized and express most of their MHC class II molecules and intercellular adhesion molecule-1 (ICAM-1) in proximity to the T cells.

Cell cooperation in the antibody response

Fig. 8.5 Antigen is presented to naive T cells by APCs such as dendritic cells. B cells also take up antigen and present it to the T cells, receiving signals from the T cells to divide and differentiate into antibody-forming cells (AFCs) and memory B cells (BM). B APC antigen T T TH B TH B B B B BM T cell priming T–B cooperation division

AFC AFC AFC

B B

differentiation

Intracellular signaling in B cell activation

Fig. 8.6 B cell activation is similar to T cell activation. If membrane immunoglobulin becomes cross-linked (e.g. by a TI antigen), tyrosine kinases, including Lck, Lyn, Fyn, and Blk, become activated. They phosphorylate the ITAM domains in the Igα and Igβ chains of the receptor complex. These can then bind another kinase, Syk, which activates phospholipase C. This acts on membrane phosphatidylinositol bisphosphate (PIP2) to generate inositol trisphosphate (IP3) and diacyl

glycerol (DAG), which activates protein kinase C. Signals from the other kinases are transduced to activate nuclear

transcription factors. integration of kinase cascades Lck PLC Ag membrane Ig

Lyn Fyn Blk Syk

DAG IP₃

PIP₂ Ig Ig

The interactions in these clusters strongly suggest an intense exchange of information, which leads to two important events in the B cell life cycle:

• induction of proliferation; and • differentiation into AFCs.

The initial interaction between a naive B cell and a

cognate antigen via the BCR in the presence of cytokines

or other growth stimuli induces activation and prolif- eration of the B cell. This then leads to processing of the TD antigen and presentation to T cells (see Chapter 7).

The interaction between B and T cells is a two-way process in which:

• B cells present antigen to T cells; and

• receive signals from the T cells for division and differentiation (Fig. 8.8).

The central antigen-specific interaction is that between the MHC class II molecule–antigen complex and the TCR. This interaction is augmented by interactions between pairs of adhesion molecules and co-stimulatory molecules. Q. Which co-stimulatory molecules, present on B cells and other APCs, promote T cell proliferation? What mechanisms are involved?

A. B7-1 (CD80) and B7-2 (CD86) act on antigen-activated T cells by ligating CD28, leading to expression of the high-affinity IL-2 receptor (see Fig. 7.16).

The interaction between B and T cells is a two-way event as follows:

• CD40, a member of the TNF receptor family, delivers a strong activating signal to B cells, more potent even than signals transmitted via surface immunoglobulin; • upon activation, T cells transiently express a ligand,

termed CD40L (a member of the TNF family), which interacts with CD40;

• CD40–CD40L interaction helps to drive B cells into cell cycle;

• transduction of signals through CD40 induces upreg- ulation of CD80/CD86 and therefore helps to provide further co-stimulatory signals to the responding T cells.

Signaling through CD40 is also essential for germinal center development and antibody responses to TD antigens.

B AND T CELL ACTIVATION FOLLOW SIMILAR PATTERNS

B cell co-receptor complex

Fig. 8.7 The B cell co-receptor complex consists of CD21 (the complement receptor type 2), CD19, and CD81 (a molecule with four transmembrane segments). Antigen with covalently bound C3b or C3d can cross-link the membrane

immunoglobulin to CD21 of the co-receptor complex. This greatly reduces the cell’s requirement for antigen to activate it. CD19 can associate with tyrosine kinases including Lyn, Fyn, Vav, and PI-3 kinase (PI-3K). Compare this with CD28 on the T cell (see Fig. 7.21). Receptor cross-linking causes

phosphorylation of the Igα and Igβ chains of the

antigen–receptor complex and recruitment and activation of Syk. Fyn/Lyn Vav/PI-3K Ag C3b C3d Igα Igβ Syk B cell co-receptor complex CD19 CD81 CD21 mlg

Cell surface molecules involved in the interaction between B and THcells

Fig. 8.8 Membrane immunoglobulin (mIg) takes up antigen (Ag) into an intracellular compartment where it is degraded and peptides can combine with MHC class II molecules. Other arrows show the discrete signal transduction events that have been established. A and B are the antigen receptor signal transduction events involving tyrosine phosphorylation and phosphoinositide breakdown. The antigen receptors also regulate LFA-1 affinity for ICAM-1 and ICAM-3, possibly through the signal transduction events. In the T cell, CD28 also sends a unique signal to the T cell (C). In the later phases of the response CTLA-4 can supplant CD28 to cause

downregulation (see Fig. 7.18). In the B cell, stimulation via CD40 is the most potent activating signal (D). In addition, MHC class II molecules appear to induce distinct signaling events (E). Not shown is the exchange of soluble interleukins and binding to the corresponding receptors on the other cell. (Adapted from DeFranco A. Nature 1991;351:603–605)

LFA-1 ICAM-1 ICAM-3 CD28 (CTLA-4) CD40L CD80/CD86 CD40 TCR CD4 Ag Ag mIg C A D E B LFA-3 p56Lck MHC class II CD2 T cell B cell

Q. Some individuals have a mutation that produces a non-