Transduction of Activating Signals Involves Iga Igp Heterodimers

For many years, immunologists questioned how engagement of the Ig receptor by antigen could activate intracellular signaling pathways. All isotypes of mIg have very short cytoplasmic tails. Both mIgM and mIgD on B cells extend into the cytoplasm by only three amino acids; the mIgA tail consists of 14 amino acids; and the mIgG and mIgE tails contains 28 amino acids. In each case, the cytoplasmic tail is too short to be able to generate a signal by associating with intracellular signaling molecules, such as tyrosine kinases and G proteins. The discovery that membrane Ig is associated with the disul-fide-linked heterodimer Ig-a/Ig-p, forming the B-cell recep-tor(BCR), solved this longstanding puzzle. Though it was originally thought that two Ig-a/Ig-p heterodimers associated with one mIg to form the B-cell receptor, careful biochemical analysis has shown that only one Ig-a/Ig-p het-

(b) TD antigen

B cell

FIGURE 11-6

Th cell

(b) TD antigen

Th cell

Thymus Dependent Antigens

B cell

CD40/CD40L

B cell

FIGURE 11-6

B cell

CD40/CD40L

An effective signal for B-cell activation involves two distinct signals induced by membrane events. Binding of a type 1 thymus-independent (TI-1) antigen to a B cell provides both signals. A thymus-dependent (TD) antigen provides signal 1 by crosslinking mIg, but a separate interaction between CD40 on the B cell and CD40L on an activated TH cell is required to generate signal 2.

erodimer associates with a single mIg molecule to form the receptor complex. (Figure 11-7). Thus the BCR is functionally divided into the ligand-binding immunoglobulin molecule and the signal-transducing Ig-a/Ig-p heterodimer. A similar functional division marks the pre-BCR, which transduces signals via a complex consisting of an Ig-a/Ig-p het-rodimer and ^ heavy chains combined with the surrogate light chain (see Figure 11-4). The Ig-a chain has a long cytoplasmic tail containing 61 amino acids; the tail of the Ig-p chain contains 48 amino acids. The cytoplasmic tails of both Ig-a and Ig-p contain the 18-residue motif termed the immunoreceptor tyrosine-based activation motif (ITAM; see Figure 11-7) which has already been described in several molecules of the T-cell-receptor complex (see Figure 10-11). Interactions with the cytoplasmic tails of Ig-a/Ig-p transduce the stimulus produced by crosslinking of mIg molecules into an effective intracellular signal.

In the BCR and the TCR, as well as in a number of receptors for the Fc regions of particular Ig classes (FceRI for IgE; Fc^RIIA, Fc^RIIC, Fc^RIIIA for IgG), ligand binding and signal transduction are mediated by a multimeric complex of proteins that is functionally compartmentalized. The ligand-binding portions of these complexes (mIg in the case of the BCR) is on the surface of the cell, and the signal-transducing portion is mostly or wholly within the cell. As is true of the TCR, signaling from the BCR is mediated by protein tyrosine kinases (PTKs). Furthermore, like the TCR, the BCR itself has no PTK activity; this activity is acquired by recruitment of a number of different kinases, from nearby locations within the cell, to the cytoplasmic tails of the signal. Phosphorylation of tyrosines within the ITAMs of the BCR by receptor associated PTKs is among the earliest events in B-cell activation and plays a key role in bringing other critical PTKs to the BCR and in their activation. The antigen-mediated crosslinking of BCRs initiates a number of signaling cascades that ultimately result in the cell's responses to the crosslinking of its surface immunoglobulin by antigen. The crosslinking of BCRs results in the induction of many signal-transduction pathways

Antigen \

B-cell membrane

Resting B cell

Crosslinked B cell

B-cell membrane

Resting B cell

Crosslinked B cell

Activating Signals Bcr

ITAM

\ Kinases

ITAM

\ Kinases

ITAM sequence

FIGURE 11-7

The initial stages of signal transduction by an activated B-cell receptor (BCR). The BCR comprises an antigen-binding mIg and one signal-transducing Ig-a/Ig-p heterodimer. Following antigen crosslinkage of the BCR, the immunoreceptor tyrosine-based activation motifs (ITAMs) interact with several members of the Src family of tyrosine kinases (Fyn, Blk, and Lck), activating the kinases. The activated enzymes phosphorylate tyrosine residues on the cytoplasmic tails of the Ig-a/Ig-p heterodimer, creating docking sites for Syk kinase, which is then also activated. The highly conserved sequence motif of ITAMs is shown with the tyrosines (Y) in blue. D/E indicates that an aspartate or a glutamate can appear at the indicated position, and X indicates that the position can be occupied by any amino acid.

and the activation of the B cell. Figure 11-8 shows many parallels between B-cell and T-cell activation. These include:

■ Compartmentalization of function within receptor subunits: Both the B-cell and T-cell pathways begin with antigen receptors that are composed of an antigen-binding and a signaling unit. The antigen-binding unit confers specificity, but has cytoplasmic tails too short to transduce signals to the cytoplasm of the cell. The signaling unit has long cytoplasmic tails that are the signal transducers of the receptor complex.

■ Activation by membrane-associated Src protein tyrosine kinases: The receptor-associated PTKs (Lck in T cells and Lyn, Blk, and Fyn in B cells) catalyze phosphorylations during the early stages of signal transduction that are essential to the formation of a functional receptor signaling complex.

■ Assembly of a large signaling complex with protein-tyrosine-kinase activity: The phosphorylated tyrosines in the ITAMs of the BCR and TCR provide docking sites for the molecules that endow these receptors with PTK activity; ZAP-70 in T cells and Syk in B cells.

■ Recruitment of other signal-transduction pathways: Signals from the BCR and TCR result in the production of the second messengers IP3 and DAG. IP3 causes the release of Ca2+ from intracellular stores, and DAG activates PKC. A third important set of signaling pathways are those governed by the small G proteins Ras and Rac that are also activated by signals received through the TCR or BCR.

■ Changes in gene expression: One of the important outcomes of signal-transduction processes set in motion with engagement of the BCR or the TCR is the generation or translocation to the nucleus of active transcription factors that stimulate or inhibit the transcription of specific genes.

Failures in signal transduction can have severe consequences for the immune system. The Clinical Focus on X-linked agammaglobulinemia describes the effect of defective signal transduction on the development of B cells.

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