UNDERSTANDING CROSS-PRESENTATION: INSIGHTS FROM COMPUTATIONAL MODELING

NIETO F; GARRIDO F; DINAMARCA S; CEBRIAN I; MAYORGA LS

San Juan

Congreso; XLI Reunión Científica Anual de la Sociedad de Biología de Cuyo; 2023

Sociedad de Biología de Cuyo

Dendritic cells (DCs) have a specialized endomembrane system capable of presenting exogenous antigens in the context of MHC class I (MHC- I) molecules. This process, named cross-presentation, is crucial to activate CD8+ T lymphocytes and initiate cytotoxic immune responses. The intracellular source of MHC-I molecules for cross- presentation is still a matter of debate. These molecules are assembled in the ER and only leave this compartment whenthey are properly loaded with peptide and associated with β-2 microglobulin. Once at the plasma membrane, the complexes can be internalized and recycled. However, part of these stable complexes can be exposed to acidic compartments that promote the unloading of peptides, providing a source of receptive MHC-I molecules. One main feature of endo/phagocytic compartments in DCs is their low degradative capacity, so resulting peptides from internalized antigens are preserved, and this favors cross-presentation. Our recent experiments suggest that increases in the pH of the cellular medium allow peptides to be loaded into MHC-I complexes more efficiently. From the analysisof the steps required in this process, it is evident that the encounter of a receptive complex and a processed peptide is strongly influenced by the dynamism of the endomembrane system. Here, organelles continuously change compositionand shape by means of fusion, maturation, and budding and fission of vesicles and tubules, so computational models are a proper tool to study these processes. We present an Agent-Based Model in combination with Ordinary DifferentialEquations with enough complexity to reproduce cross-presentation. The model embraces the secretory and endocytic pathways, in connection with the plasma membrane, the endoplasmic reticulum, and the cytosol. Key molecules required for cross-presentation were included as cargoes. In the simulations, the kinetics of MHC-I uptake and recycling, and cross-presentation accurately reproduced experimental values. The model proved to be a suitable tool to elaborate hypotheses and design experiments.