Extensive CD4 and CD8 T Cell Cross-Reactivity between Alphaherpesviruses

• Published in: The Journal of immunology (1950) 2016-03, Vol.196 (5), p.2205-2218
• Main Authors: Jing, Lichen, Laing, Kerry J, Dong, Lichun, Russell, Ronnie M, Barlow, Russell S, Haas, Juergen G, Ramchandani, Meena S, Johnston, Christine, Buus, Soren, Redwood, Alec J, White, Katie D, Mallal, Simon A, Phillips, Elizabeth J, Posavad, Christine M, Wald, Anna, Koelle, David M
• Format: Article
• Language: English
• Subjects: Alphaherpesvirinae - immunology; Antigen Presentation - immunology; Antigens, Viral - immunology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cross Reactions - immunology; Cytokines - metabolism; Epitopes, T-Lymphocyte - immunology; Herpesviridae Infections - genetics; Herpesviridae Infections - immunology; Herpesviridae Infections - virology; Herpesvirus 1, Human - immunology; Herpesvirus 2, Human - immunology; Humans; Peptides - immunology; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Viral Proteins - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1502366

The Alphaherpesvirinae subfamily includes HSV types 1 and 2 and the sequence-divergent pathogen varicella zoster virus (VZV). T cells, controlled by TCR and HLA molecules that tolerate limited epitope amino acid variation, might cross-react between these microbes. We show that memory PBMC expansion with either HSV or VZV enriches for CD4 T cell lines that recognize the other agent at the whole-virus, protein, and peptide levels, consistent with bidirectional cross-reactivity. HSV-specific CD4 T cells recovered from HSV-seronegative persons can be explained, in part, by such VZV cross-reactivity. HSV-1-reactive CD8 T cells also cross-react with VZV-infected cells, full-length VZV proteins, and VZV peptides, as well as kill VZV-infected dermal fibroblasts. Mono- and cross-reactive CD8 T cells use distinct TCRB CDR3 sequences. Cross-reactivity to VZV is reconstituted by cloning and expressing TCRA/TCRB receptors from T cells that are initially isolated using HSV reagents. Overall, we define 13 novel CD4 and CD8 HSV-VZV cross-reactive epitopes and strongly imply additional cross-reactive peptide sets. Viral proteins can harbor both CD4 and CD8 HSV/VZV cross-reactive epitopes. Quantitative estimates of HSV/VZV cross-reactivity for both CD4 and CD8 T cells vary from 10 to 50%. Based on these findings, we hypothesize that host herpesvirus immune history may influence the pathogenesis and clinical outcome of subsequent infections or vaccinations for related pathogens and that cross-reactive epitopes and TCRs may be useful for multi-alphaherpesvirus vaccine design and adoptive cellular therapy.