Th Cells Play Essential Roles in Most BCell Responses

As noted already, activation of B cells by soluble protein antigens requires the involvement of TH cells. Binding of antigen to B-cell mIg does not itself induce an effective competence signal without additional interaction with membrane molecules on the TH cell. In addition, a cytokine-mediated progression is required for B-cell proliferation. Figure 11-10 outlines the probable sequence of events in B-cell activation by a thymus-dependent (TD) antigen. This process is considerably more complex than activation induced by thymus-independent (TI) antigens.

FORMATION OF T-B CONJUGATE

After binding of antigen by mIg on B cells, the antigen is internalized by receptor-mediated endocytosis and processed within the endocytic pathway into peptides. Antigen binding also initiates signaling through the BCR that induces the B cell to up-regulate a number of cell-membrane molecules, including class II MHC molecules and the co-stimulatory ligand B7 (see Figure 11-10a). Increased expression of both of these membrane proteins enhances the ability of the B cell to function as an antigen-presenting cell in TH-cell activation. B-cells could be regarded as helping their helpers because the antigenic peptides produced within the endocytic processing pathway associate with class II MHC molecules and are presented on the B-cell membrane to the TH cell, inducing its activation. It generally takes 30-60 min after inter-nalization of antigen for processed antigenic peptides to be displayed on the B-cell membrane in association with class II MHC molecules.

Because a B cell recognizes and internalizes antigen specifically, by way of its membrane-bound Ig, a B cell is able to present antigen to TH cells at antigen concentrations that are 100 to 10,000 times lower than what is required for presentation by macrophages or dendritic cells. When antigen concentrations are high, macrophages and dendritic cells are effective antigen-presenting cells, but, as antigen levels drop, B cells take over as the major presenter of antigen to TH cells.

Once a TH cell recognizes a processed antigenic peptide displayed by a class II MHC molecule on the membrane of a

(a) Antigen crosslinks mIg, generating signal (T), which leads to increased expression of class II MHC and co-stimulatory B7. Antigen-antibody complexes are internalized by receptor-mediated endocytosis and degraded to peptides, some of which are bound by class II MHC and presented on the membrane as peptide-MHC complexes.

(b) Th cell recognizes antigen-class II MHC on B-cell membrane. This plus co-stimulatory signal activates Th cell.

(c) 1. Th cell begins to express CD40L.

2. Interaction of CD40 and CD40L provides signal (2).

3. B7-CD28 interactions provide co-stimulation to the Th cell.

(d) 1. B cell begins to express receptors for various cytokines. 2. Binding of cytokines released from Th cell in a directed fashion sends signals that support the progression of the B cell to DNA synthesis and to differentiation.

CD40

CD40

Th cell

CD40

Th cell

CD40 CD40L

CD40 CD40L

j Cytokines j Cytokines

Activated B cell

Proliferating B cells

Mitosis

Proliferating B cells

FIGURE 11-10

Sequence of events in B-cell activation by a thymus-dependent antigen. The cell-cycle phase of the interacting B cell is indicated on the right.

B cell, the two cells interact to form a T-B conjugate (Figure 11-11). Micrographs of T-B conjugates reveal that the TH cells in antigen-specific conjugates have reorganized the Golgi apparatus and the microtubular-organizing center toward the junction with the B cell. This structural adjustment facilitates the release of cytokines toward the antigen-specific B cell.

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