Mathematical modeling of T cell clustering following malaria infection in mice

Malaria is the result of the immune system's unsuccessful clearance of hepatocytes (liver cells) infected by the eukaryotic pathogen of the Plasmodium genus. It has been shown that CD8 T cells are required and sufficient for protective immunity against malaria in mice [29, 36], but the mechanisms by which they find and eliminate infected hepatocytes are not known yet. Recently we reported the formation of CD8 T cell clusters consisting of up to 25 cells around infected cells [8]. Our mathematical modeling and data analysis revealed that malaria-specific T cells likely recruit each other and also non-malaria-specific T cells to infected hepatocytes in a process that is G-protein-coupled receptor (GPCR) dependent. Evidence exists for variable T-cell extrinsic factors in explaining the large variation of cluster sizes around infected cells, for which we propose further experiments to discriminate between T-cell-dependent and -independent mechanisms in cluster formation. Our results suggest that CD8 T cells specific to an ongoing infection tend to cluster around infected cells and their presence also enhances irrelevant CD8 T cells' propensity to clustering. However, analysis of T cell movement tracks shows that irrelevant T cells have a significantly lower average frequency of movements towards the parasite than antigen-specific T cells. Since clusters of CD8 T cells might be more efficient at killing infected cells than a CD8 T cell alone, understanding the requirements for large T cell clusters might have important implications in the fields of immunology and medicine.