The relationship between antigen concentration, antigen internalization, and antigenic complexes: modeling insights into antigen processing and presentation.

Abstract

Abstract. Native antigen is processed and subsequently presented on the surface of antigen-presenting cells, an important step in the elicitation of an immune response. The early events of antigen processing and presentation include: ingestion of a native antigen, intracellular degradation to expose an antigenic peptide fragment, binding of this fragment with an MHC class U molecule, and display of this newly formed complex on the cell surface. Through the development of a mathematical model, a set of mathematical equations which describes the time-dependent appearance, disappearance, and movement of individual molecules, quantitative insight can be gained into the pathways and rate-limiting steps of antigen presentation.The credibility of the model has been verified by comparison to literature data. For example, it has been shown experimentally that macrophages require 60 min for effective antigen presentation, whereas B cells require 6-8 h. The mathematical model predicts these presentation times and identifies the difference in the cell's respective pinocytic rates and sizes as important parameters. B cells capture antigen in their environment through nonspecific fluid-phase pinocytosis as well as by binding antigen to their surface immunoglobulin, allowing receptor-mediated uptake. Uptake of antigen via receptor-mediated endocytosis has been reported to require 1,000-fold less antigen than uptake via nonspecific pinocytosis. The mathematical model clearly predicts this decrease in concentration. The model also makes quantitative predictions for the number of MHC class H-antigen complexes needed to produce T cell stimulation. T HE recognition of complex antigens by T helper cellsrequires the participation of accessory cells. These accessory ceils, termed antigen-presenting cells (APC), prepare the antigen for recognition by the T cell. The APC, commonly a B cell or macrophage, ingests the extracellular antigen, processes it so as to expose an immunogenic peptide sequence, and expresses this fragment on its membrane surface in a complex with the proper genetic restriction molecule, an MHC class II molecule (Ia). It is believed that the antigen, in the context of this complex, can then be recognized by the T cell receptor (Watts and McConnell, 1987;Allen et al., 1987). This series of events is commonly referred to as antigen processing and presentation (Moiler, 1978;Unanue, 1984;Chesnut and Grey, 1985).Recent experiments have provided data on the ingestion of a native antigen, the intracellular processing of that antigen in an acidic compartment, and the surface expression of the MHC class if-antigen (Ia-Ag) complex. Yet many unanswered questions remain regarding the initial interaction of antigen with APC. For example, literature data relating anti-1. Abbreviations used in this paper: APC, antigen-presenting cell; Ag, antigenie peptide fragment; FPP, fluid-phase pinocytosis; RME, receptormediated endocytosis.gen concentration with subsequent T cell response, typically assayed by measuring IL 2 secretion or tri...

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