Characterization of CTLA4 trafficking and implications for its function
CTLA4 is an essential negative regulator of T cell immune responses. This receptor is constitutively presented by regulatory T cells and regulates the expression of costimulatory molecules on antigen presenting cells. CTLA4 is an important target of checkpoint inhibitors in cancer. Endocytosis of CTLA4 is continuous and rapid with subsequent recycling and degradation. Upon ligation with costimulatory molecules, CTLA4 can remove the ligands from opposing cells by a process termed transendocytosis. In cooperation with Lucy Walker and David Sansom (UCL, London, UK), we studied the impact of this cell extrinsic mechanism on the regulation of T cell immune response. We described the trafficking of transmembrane molecules and in vitro staining via mathematical modeling, which allows to estimate the kinetics of different trafficking sub-processes from confocal microscopy and FACS data via parameter estimation algorithms.
As a use case of our model, we analyzed the kinetics of ligand uptake by varying binding affinities, identifying how efficient and how long different ligands, such as natural ligands or checkpoint inhibitors, are able to block CTLA4. Surprisingly, the results suggest that ligand uptake is optimally fast for an intermediate affinity range, and very inefficient for high and low affinities. This nonlinear relationship between the extent/duration of CTLA4 block and ligand affinities could support optimising anti-CTLA4 therapeutic designs. Our combined in vitro and in silico approach is broadly applicable beyond the current scope and can be employed to characterize inter- and intra-cellular trafficking of different transmembrane molecules.
Philippe Robert (former member), Jesus D. Badillo Herrera, Michael Meyer-Hermann
David Sansom, Lucy Walker (UCL, London)
Khailaie S, Rowshanravan B, Robert PA, Waters E, Halliday N, Badillo Herrera JD, Walker LSK, Sansom* DM, Meyer-Hermann* M. Characterization of CTLA4 trafficking and implications for its function. Biophys J 2018 Oct 2; 115(7):1330-1343. [*shared corresponding author].
DFG, Human Frontier Science Program
- Systems Immunology- Prof. Dr. Michael Meyer-Hermann