Date Published: June 20, 2013
Publisher: Public Library of Science
Author(s): Virginie Feliu, Virginie Vasseur, Harshita S. Grover, H. Hamlet Chu, Mark J. Brown, Jeremy Wang, Jon P. Boyle, Ellen A. Robey, Nilabh Shastri, Nicolas Blanchard, Eric Y. Denkers.
CD8 T cells protect the host from disease caused by intracellular pathogens, such as the Toxoplasma gondii (T. gondii) protozoan parasite. Despite the complexity of the T. gondii proteome, CD8 T cell responses are restricted to only a small number of peptide epitopes derived from a limited set of antigenic precursors. This phenomenon is known as immunodominance and is key to effective vaccine design. However, the mechanisms that determine the immunogenicity and immunodominance hierarchy of parasite antigens are not well understood.
CD8 T cells play a critical role in immune-mediated protection against intracellular apicomplexan parasites. Antigenic determinants recognized by CD8 T cells are short peptides of 8 to 10 amino acids presented by class I molecules of the major histocompatibility complex (MHC I). Antigenic peptides are typically degraded by cytosolic proteasomes, transported into the endoplasmic reticulum (ER), trimmed by ER-resident aminopeptidases and loaded on peptide-receptive MHC I molecules . The spectrum of peptides that can theoretically be presented by a given MHC I is far larger than the peptides that actually elicit CD8 T cell responses. Furthermore, not all the peptide-MHC I complexes that can be recognized are equal: rather they elicit a hierarchy of specific CD8 T cells. This phenomenon of “selection and ranking” is termed immunodominance. Immunodominant peptide-MHC I elicit the most abundant cognate T cell populations, whereas subdominant peptide-MHC I induce less abundant T cells (reviewed in , ). Knowledge of the mechanisms that enhance immunogenicity and determine immunodominance hierarchy is central to design of optimal vaccines.
In this study, we have identified the molecular bases underlying the marked immunodominance of a CD8 T cell response that controls the intracellular T. gondii parasite. Rather than peptide affinity for MHC I and naïve T cell frequency, we find that immunodominance is determined by the location of the epitope within the antigenic precursor.