Modeling Fine-Tuned Affinity

Abstract

A combination of experimental analysis with mathematical modeling has yielded new insights into the fundamental molecular interactions by which the immune system reacts to peptide antigens presented to T lymphocytes by antigen-presenting cells (APCs). The critical interaction takes place between peptide bound to major histocompatibility complex (pMHC) on the surface of APCs, which binds to T cell receptors (TCRs) on the 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, the series of biochemical steps needed for activation is not completed, so a minimum affinity must be achieved. However, too high an affinity is not optimal. The system must respond to exceedingly small amounts of pathogen-derived molecules, so pMHC molecules are thought to be amplified by serial interaction with multiple TCRs. Thus weaker binding can be advantageous to signaling. Coombs et al. 's mathematical modeling of pMHC-TCR interactions supported the concept of an ideal range of affinities for activation. They also derive important testable new hypotheses from their experiments and modeling: Internalization of TCRs appears to require recognition of TCRs that have interacted with pMHC, but have since dissociated--presumably producing an altered biochemical state of the TCR that would last for minutes after dissociation. Also, the modeling suggests that 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. C. Coombs, A. M. Kalergis, S. G. Nathenson, C. Wofsy, B. Goldstein, Activated TCRs remain marked for internalization after dissociation from pMHC. Nature Immunol. 3 926-931 (2002). [Online Journal]