The Problem of Ligand Concentration tion, the basic vocabulary for understanding events at Second, the number of specific ligands for a particular the cell surface and how these events regulate the sig-TCR on an APC is very small (Demotz et al., 1990; Harnaling machinery is in a nascent stage. Recently, several ding and Unanue, 1990). Low concentration of ligand new concepts have been introduced into the literature. further complicates the problem of low affinity. The func-These concepts, particularly those of two-dimensional tion of the APC is to process and display proteins conaffinity, serial TCR triggering, and kinetic proofreading, tained in both the intracellular and extracellular environare likely to transform the way in which we think about ment for display on the cell surface (Cresswell, 1994). T cell activation (Dustin et al., 1996a; McKeithan, 1995; T cells monitor these peptides for the presence of a

Valitutti et al., 1995). Understanding protein interactions‘‘foreign’’peptide. Given the large spectrum of proteins in membranes is a new frontier in biology and is a general in the cellular environment, the MHC, at any given time, area in which the T cell activation system is poised to is bound to a tremendous number of different peptides take the lead.(Falk et al., 1991). Therefore, the number of MHC mole-Here, we will discuss recent work on this area, define cules containing the exact same peptide is likely to be some key questions, and present a topological model very low. In addition, as these specific ligands are probaof T cell activation. A key feature of this model is the bly randomly distributed on surface of the APC, only a idea that engagement of the TCR by antigen does not small fraction of a specific antigenic ligand is likely to directly result in T cell activation. Rather, it is the re- be initially present in the area of cell contact between arrangement of membrane proteins in the area of con- the T cell and the APC. Are there specific mechanisms tact between the T cell and the antigen-presenting cell that existto facilitate the detection of low concentrations (APC) that is the critical event. Topological features of of specific antigen by the TCR?