Public TCR use by herpes simplex virus-2-specific human CD8 CTLs

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• T-cell receptors (TCRs) are crucial for recognizing peptide-MHC complexes, with germline alpha and beta genes recombining to form these receptors.
• Long-term exposure to antigens, such as during chronic herpes simplex virus (HSV) infections, can influence the T-cell repertoire over time.

Purpose of the Study:

• To investigate the CD8 T-cell response to HSV-2 in chronically infected individuals.
• To identify specific T-cell receptor (TCR) sequences and their characteristics involved in recognizing an immunodominant HSV-2 epitope.

Main Methods:

• Sequencing of hypervariable regions of TCR alpha and beta chains from T-cell clones recognizing HSV-2 virion protein 22 aa 49-57.
• Analysis of TCR gene segment usage, including TCRBV12-4, and T-cell clone public sequences.
• Ex vivo staining of peripheral blood mononuclear cells (PBMCs) with a TCRBV12 monoclonal antibody (mAb) and tetramer-binding cells.

Main Results:

• TCRBV12-4 was the most frequently detected TCRBV gene segment across subjects and T-cell clones.
• A significant percentage of tetramer-binding cells in PBMCs were identified using a TCRBV12 mAb.
• Three public alpha-chain and three public beta-chain TCR sequences, along with public heterodimers, were shared among individuals, indicating convergent T-cell responses.

Conclusions:

• The CD8 T-cell response to a dominant alpha-herpesvirus epitope converges on preferred TCR sequences.
• A specific TCRVA1-1 sequence showed promiscuous pairing with various TCRB polypeptides, suggesting a dominant structural role for the alpha chain.
• Functional avidity for cytotoxicity and IFN-gamma release was generally invariant, except in one subject with unique TCR sequences and lower viral shedding.