The surface organization of MHC class I molecules regulates their recognition by T-cells

MHC Class I molecules present intracellular peptides on the cell surface for interrogation by CD8+-restricted cytotoxic T lymphocytes. Efficient presentation depends upon agonist peptide concentration as well as proper MHC class I (MHC I) context and organization at the cell surface. Organization of MHC can modulate the T-cell response.; MHC organization can be modulated by global changes in the membrane skeleton. Disrupting the actin cytoskeleton mobilizes MHC I while stabilizing actin immobilizes it. Changes in actin structure can be achieved by direct drug treatment or through disruption of membrane cholesterol levels. Depleting cholesterol mobilized pools of PIP2 inducing actin remodeling through gelsolin, ∝-actinin, and NWASP. PIP2 also plays a role in regulating the response of target cells to cytolytic T-cells during killing.; Changing MHC I organization, through changes in homoclustering, modulates antigen presentation. Cholesterol depletion or direct crosslinking of MHC I molecules induces larger clusters on the surface. These clusters enhance presentation of low concentrations of agonist peptide. I propose that clustering provides a mechanism to discern agonist peptide from null and antagonist forms. This enables T-cells, and in particular naive T-cells, to respond only to unique and highly-specific antigen.