Lack of functional TCR-epitope interaction is associated with herpes zoster through reduced downstream T cell activation.

The role of T cell receptor (TCR) diversity in infectious disease susceptibility is not well understood. We use a systems immunology approach on three cohorts of herpes zoster (HZ) patients and controls to investigate whether TCR diversity against varicella-zoster virus (VZV) influences the risk of HZ. We show that CD4⁺ T cell TCR diversity against VZV glycoprotein E (gE) and immediate early 63 protein (IE63) after 1-week culture is more restricted in HZ patients. Single-cell RNA and TCR sequencing of VZV-specific T cells shows that T cell activation pathways are significantly decreased after stimulation with VZV peptides in convalescent HZ patients. TCR clustering indicates that TCRs from HZ patients co-cluster more often together than TCRs from controls. Collectively, our results suggest that not only lower VZV-specific TCR diversity but also reduced functional TCR affinity for VZV-specific proteins in HZ patients leads to lower T cell activation and consequently affects the susceptibility for viral reactivation. [Display omitted] • T cell phenotypes did not significantly differ between HZ patients and controls • CD4⁺ TCR diversity against VZV gE and IE63 after culture was broader in controls • T cell activation pathways after VZV peptide stimulation were lower in HZ patients • TCRs from HZ patients co-clustered more often together than TCRs from controls Boeren et al. demonstrate that susceptibility for shingles, caused by varicella-zoster virus (VZV) reactivation, correlates with reduced T cell receptor (TCR) diversity against several VZV proteins. Their results indicate that reduced T cell activation correlates with reduced affinity between VZV proteins and the VZV-specific TCR repertoire in shingles patients. [ABSTRACT FROM AUTHOR]