Affinity of TCR for PeptideMHC Complexes Is Weak Compared with Antibody Binding

The affinity of T-cell receptors for peptide-MHC complexes is low to moderate, with Kd values ranging from 10"4 to 10"7 M. This level of affinity is weak compared with antigen-antibody interactions, which generally have Kd values ranging from 10"6 to 10"10 M (Figure 9-12a). However, T-cell interactions do not depend solely on binding by the TCR; cell-adhesion molecules strengthen the bond between a T cell and an antigen-presenting cell or a target cell. Several accessory membrane molecules, including CD2, LFA-1, CD28, and CD45R bind independently to other ligands on antigen-presenting cells or target cells (see Table 9-4 and Figure 9-12b). Once cell-to-cell contact has been made by the adhesion molecules, the T-cell receptor may scan the membrane for peptide-MHC complexes. During activation of a T cell by a particular peptide-MHC complex, there is a transient increase in the membrane expression of

Weak

T-cell receptors

Strong binding

Adhesion Molecules

10-9

Growth Factor Receptors

Affinity constant "(mol/L)

Antibodies

Th cell

Antigen-presenting cell

LFA-1

TCR-CD3

CD4 CD45R CD28

Antigen-presenting cell

LFA-1

TCR-CD3

CD4 CD45R CD28

Lfa1 Tcr Cd3

CD22 B7

Role of coreceptors in TCR binding affinity. (a) Affinity constants for various biologic systems. (b) Schematic diagram of the interactions between the T-cell receptor and the pep-tide-MHC complex and of various accessory molecules with their ligands on an antigen-presenting cell (left) or target cell (right).

CD22 B7

TC cell

Target cell

TCR-CD3

CD8 CD45R

Target cell

TCR-CD3

CD8 CD45R

Coreceptors Cell Binding Affinity

Binding of the coreceptors CD4 and CD8 and the other accessory molecules to their ligands strengthens the bond between the interacting cells and/or facilitates the signal transduction that leads to activation of the T cell.

FIGURE 9-12

Role of coreceptors in TCR binding affinity. (a) Affinity constants for various biologic systems. (b) Schematic diagram of the interactions between the T-cell receptor and the pep-tide-MHC complex and of various accessory molecules with their ligands on an antigen-presenting cell (left) or target cell (right).

Binding of the coreceptors CD4 and CD8 and the other accessory molecules to their ligands strengthens the bond between the interacting cells and/or facilitates the signal transduction that leads to activation of the T cell.

Cell Transduction

FIGURE 9-13

Chain Weak

FIGURE 9-13

Three-dimensional structures for the TCR-MHC-peptide complex. (a) Model showing the interaction between the human TCR (top, yellow) and the HLA-A2 class I MHC molecule (bottom, blue) with bound HTLV-I Tax peptide (white and red). (b) Backbone tube diagram of the ternary complex of mouse TCR bound to the class I MHC H-2Kb molecule and peptide (green tube numbered P1-P8). CDR1 and 2 of the TCR a-chain variable domain (Va) are colored pink; CDR 1 and 2 of the p-chain variable domain (Vp) are blue, and the CDR3s of both chains are green. The HV4 of the p chain is orange. (c) MHC molecule viewed from above (i.e., from top of part (a), with the hypervariable loops (1 -4)

of the human TCR a (red) and p (yellow) variable chains superimposed on the Tax peptide (white) and the a1 and a2 domains of the HLA-A2 MHC class I molecule (blue). (d) CDR regions of mouse TCR a and p chains viewed from above, showing the surface that is involved in binding the MHC-peptide complex. The CDRs are labeled according to their origin (for example, a1 is CDR1 from the a chain). HV4 is the fourth hypervariable region of the p chain. [Parts (a) and (c) from D. N. Garboczi et al., 1996, Nature 384:134- 141, courtesy of D. C. Wiley, Harvard University; parts (b) and (d) from C. Garcia et al., 1996, Science 274:209, courtesy of C. Garcia, Scripps Research Institute.]

cell-adhesion molecules, causing closer contact between the interacting cells, which allows cytokines or cytotoxic substances to be transferred more effectively. Soon after activation, the degree of adhesion declines and the T cell detaches from the antigen-presenting cell or target cell. Like CD4 and CD8, some of these other molecules also function as signal-transducers. Their important role is demonstrated by the ability of monoclonal antibodies specific for the binding sites of the cell-adhesion molecules to block T-cell activation.

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