A quantitative investigation of the events of antigen processing and presentation.

Abstract

Cellular immune responses are mediated by the interaction of T-lymphocyte receptors with the bi-molecular complex formed between foreign antigen (Ag) and syngeneic molecules (MHC) on an antigen presenting cell (APC) surface. Antigens in association with MHC Class II molecules are involved in the stimulation of T-helper lymphocytes. A mathematical model of the molecular trafficking kinetics occurring in the formation and subsequent presentation of MHC-Ag complexes by APC has been developed. Specifically, the model has demonstrated that the rate constant for internalization characterizes the time frame for antigen processing in macrophage and B-cell APC. The affinity between available surface receptors and antigen determines the number of surface complexes. The model has also demonstrated the necessity for MHC recycling for efficient presentation of complexes. The mathematical model predicts $\approx$2000 MHC-Ag complexes/cell for maximal T-cell stimulation, consistent with reported data. Experimental analysis of peptide antigen uptake and retention with APC has shown peptide antigen association with APC to be different from simple fluid phase uptake. To develop a complete understanding of the cellular response, as assayed by lymphokine secretion, the events of antigen processing and presentation must be coupled to an analysis of cell-cell adhesion which facilitates the transmission of the signals needed for T-cell activation. A qualitative description of lymphokine secretion as a function of APC number and antigen dose is evaluated. The model framework shows that the APC determines the characteristic IL-2 secretion response by the T-cell and suggests methods of intervention for upregulating as well as downregulating the cellular immune response.