Antigen processing and presentation: how can a foreign antigen be recognized in a sea of self proteins?

Abstract

A mathematical model describing the time-dependent events of antigen processing and presentation is utilized to quantitatively analyze the importance of newly synthesized Ia molecules as well as Ia molecules internalized from the cell surface in the formation of Ia-antigen complexes, the T cell receptor ligand. It has recently been shown that antigen presenting cells are not selective for the proteins they process and present. Therefore, we also investigate the ability of macrophages and B cells to process and present antigen in the presence of competing proteins often present in the extracellular environment. A set of criteria is formulated based upon experimental data to determine the validity of two model variations. We draw two major conclusions from our simulations. First, we determine that macrophages and B cells can present between 1-3 Ia-antigen complexes micron-2 for antigen concentrations in the range of 4-7 microM while in the presence of approximately 0-10 microM competing proteins or peptides. Second, we find it likely that antigen presenting cells, both B cells and macrophages, need to internalize Ia molecules from the cell surface in order for a sufficient number of Ia-antigen complexes to be presented. Binding of antigen to newly synthesized Ia alone does not, given experimentally reported values for Ia synthesis, allow sufficient Ia-antigen complex formation.