EXPLORING pH-DEPENDENT CROSS-PRESENTATION: PERSPECTIVES FROM AN AGENT-BASED MODEL OF DENDRITIC CELL ENDOMEMBRANE DYNAMICS

FRANCO NIETO; FACUNDO GARRIDO; SOFÍA DINAMARCA; IGNACIO CEBRIÁN; LUIS S. MAYORGA

Córdoba

Congreso; Congreso SAIB 2024; 2024

SAIB

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. 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 show that increases in the pH of the cellular medium increase the cross-presentation of particulate antigens. Through the characterization of the antigen containing phagosomes, we have found that increasing the pH of the medium not only delays the degradation of peptides but also, the maturation of these organelles. Furthermore, the results suggest that the MHC-I complexes would be more efficiently loaded with antigenic peptides in a higher pH context. It is evident that this process is strongly influenced by the dynamism of the endomembrane system. Here, organelles continuously change composition and 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 Differential Equations with enough complexity to reproduce cross-presentation in the context of alkalized phagosomes. 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. The model proved to be a suitable tool to elaborate hypotheses and design experiments.