Expansion of the HSV-2-specific T cell repertoire in skin after immunotherapeutic HSV-2 vaccine

• Published in: JCI insight 2024-06, Vol.9 (14)
• Main Authors: Ford, Emily S, Li, Alvason Z, Laing, Kerry J, Dong, Lichun, Diem, Kurt, Jing, Lichen, Mayer-Blackwell, Koshlan, Basu, Krithi, Ott, Mariliis, Tartaglia, Jim, Gurunathan, Sanjay, Reid, Jack L, Ecsedi, Matyas, Chapuis, Aude G, Huang, Meei-Li, Magaret, Amalia S, Johnston, Christine, Zhu, Jia, Koelle, David M, Corey, Lawrence
• Format: Article
• Language: English
• Subjects: Adult; CD4-Positive T-Lymphocytes - immunology; Female; Herpes Genitalis - immunology; Herpes Genitalis - prevention & control; Herpes Genitalis - virology; Herpesvirus 2, Human - immunology; Humans; Male; Middle Aged; Receptors, Antigen, T-Cell, alpha-beta - genetics; Receptors, Antigen, T-Cell, alpha-beta - immunology; Skin - immunology; Skin - virology; Vaccination
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.179010

The skin at the site of HSV-2 reactivation is enriched for HSV-2-specific T cells. To evaluate whether an immunotherapeutic vaccine could elicit skin-based memory T cells, we studied skin biopsies and HSV-2-reactive CD4+ T cells from PBMCs by T cell receptor (TCR) β chain (TRB) sequencing before and after vaccination with a replication-incompetent whole-virus HSV-2 vaccine candidate (HSV529). The representation of HSV-2-reactive CD4+ TRB sequences from PBMCs in the skin TRB repertoire increased after the first vaccine dose. We found sustained expansion after vaccination of unique, skin-based T cell clonotypes that were not detected in HSV-2-reactive CD4+ T cells isolated from PBMCs. In one participant, a switch in immunodominance occurred with the emergence of a TCR αβ pair after vaccination that was not detected in blood. This TCRαβ was shown to be HSV-2 reactive by expression of a synthetic TCR in a Jurkat-based NR4A1 reporter system. The skin in areas of HSV-2 reactivation possessed an oligoclonal TRB repertoire that was distinct from the circulation. Defining the influence of therapeutic vaccination on the HSV-2-specific TRB repertoire requires tissue-based evaluation.