Viral variant evades CD8+ T cell immunity following suboptimal antigen recognition and activation of responding effectors (154.26)

Abstract

Abstract Evasion of the CD8+ T cell response by mutating a dominant epitope is a common evasion strategy employed by many viruses. Citing the lack of a measurable antigen-specific CTL response, it is thought that this strategy allows for the virus to persist undetected by anti-viral effectors. Using an LCMV viral escape mutant, 35A, which contains a single amino acid mutation in the H-2Db restricted, gp33-43 CD8+ T cell epitope, we show that antigen specific P14 CD8+ T cells recognize the mutant antigen and mount an early response. Despite showing greatly reduced affinity for the presenting MHC class I molecule by RMAS assay, both in-vivo and in vitro data show that P14s undergo early proliferation in response to the mutated epitope but are sub-optimally stimulated as evidenced by lower levels of cell markers CD25 and CD28, increased apoptosis, and negligible IL-2 production. P14s responding to 35A also maintain a sustained level of SHP-1 phosphatase activity pointing to the initiation of a negative regulatory pathway that aborts full activation. In contrast to the viral escape mutation being ignored by antigen specific T cells, these observations show an active mechanism by which epitope mutation prevents the accumulation of a robust antigen specific CD8+ T cell response.