Using a combination of experimental analysis and mathematical modeling, Coombs et al. have investigated the fundamental molecular interactions by which the immune system reacts to peptide antigens. The critical interaction is that of peptide bound to major histocompatibility complex (pMHC) on the surface of antigen-presenting cells, which binds to T cell receptors (TCRs) on T lymphocytes. However, T cell activation requires that the affinity of this interaction be just right. If the TCR does not remain bound to pMHC long enough, activation is not completed. However, too high an affinity is not optimal because the system must respond to exceedingly small amounts of pathogen-derived molecules. pMHC molecules are thought to be amplified by serial interaction with multiple TCRs; thus, weaker binding can be advantageous to signaling. Modeling of pMHC-TCR interactions supports the concept of an ideal range of affinities for activation. Internalization of TCRs appears to require recognition of TCRs that have interacted with pMHC but have since dissociated, presumably producing biochemical changes in the TCR. Also, differences in cross-reactivity of naïve and mature T cells may be mediated by changes in amounts of intracellular signaling molecules that are available to interact with the TCR. -- LBR
Nature Immunol. 3, 926 (2002).
