Extensive CD4 and CD8 T Cell Cross-Reactivity between Alphaherpesviruses

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• The Alphaherpesvirinae subfamily, including HSV-1, HSV-2, and VZV, are significant human pathogens.
• T cell recognition, governed by TCR and HLA, allows for some tolerance to epitope variation, suggesting potential cross-reactivity between related viruses.

Purpose of the Study:

• To investigate the extent and mechanisms of T cell cross-reactivity between HSV and VZV.
• To identify specific cross-reactive epitopes and assess their potential utility in vaccine design and therapy.

Main Methods:

• Expansion of memory peripheral blood mononuclear cells (PBMCs) with HSV or VZV.
• Analysis of CD4 and CD8 T cell responses at whole-virus, protein, and peptide levels.
• TCR sequencing and cloning to confirm cross-reactivity and identify epitope-specific T cell receptors.

Main Results:

• Bidirectional cross-reactivity was observed between HSV- and VZV-specific T cells.
• HSV-specific T cells from seronegative individuals showed VZV cross-reactivity, and vice versa.
• Identified 13 novel CD4 and CD8 HSV-VZV cross-reactive epitopes, with cross-reactivity estimated between 10-50%.

Conclusions:

• Host immune history with herpesviruses can influence responses to subsequent infections or vaccinations.
• Cross-reactive epitopes and T cell receptors offer potential for multi-alphaherpesvirus vaccine development and adoptive cellular therapies.