A Compensatory CD8+T Cell Response In C57BL/6 Mice Trigeminal Ganglia Following Ocular Infection With HSV-1 Lacking The Immunodominant Epitope

Abstract

Purpose: : Latent infection by herpes simplex virus type 1 (HSV-1) induces ganglionic infiltration by HSV-1-specific CD8⁺ T cells that can block HSV-1 reactivation from latency. Bolstering CD8⁺ T cell responses may reduce the incidence of recurrent HSV-1 disease including herpes keratitis. It is important to understand the viral antigens recognized by these CD8⁺ T cells and how mutations in viral proteins influence the dominance hierarchy of that response. Half of the CD8⁺ T cells in infected trigeminal ganglia (TG) of C57BL/6 mice recognize an immunodominant epitope on HSV-1 glycoprotein B (gB_498-505): the other 50% recognize subdominant epitopes on 11 viral proteins. The goal of this study was to determine how mutating the immunodominant epitope would influence the specificity of CD8⁺ T cells in infected TG.

Methods: : We created HSV-1 mutated in the gB_498-505 epitope and characterized their replication competence, recognition by gB_498-505-specific CD8⁺ T cells, pathogenesis and latency establishment in vivo, and the size and specificity of the TG associated CD8⁺ T cell response. TG were removed 8 days after corneal infection with the mutant viruses, and the phenotype and function of the ganglion-resident CD8⁺ T cells was determined by immunofluorescence staining for surface markers and intracellular cytokines or with tetramers.

Results: : Two of 8 mutant HSV-1 altered in the gB_498-505 epitope (F5L and L8A) exhibited wild type replication in vivo and in vitro, pathogenicity, and establishment of latency. They did not induce a gB_498-505-specific CD8⁺ T cell response but induced CD8⁺ T cell TG infiltrates of comparable size to that induced by wild type HSV-1. The size of the infiltrate was maintained by a selective compensatory increase in CD8⁺ T cells specific for certain subdominant epitopes without apparent emergence of cryptic epitopes.

Conclusions: : We conclude that mutations that eliminate the strongly immunodominant HSV-1 gB_498-505 epitope do not alter the size of the HSV-specific CD8⁺ T cell response, nor broaden the TCR repertoire through emergence of cryptic epitopes. Rather, a more even dominance hierarchy emerges with several formally subdominant epitopes rising to co-dominance. Whether this more balanced repertoire would provide more or less efficient protection remains to be determined.

Keywords: herpes simplex virus • protective mechanisms • immunomodulation/immunoregulation