T-cell immunity to human alphaherpesviruses

Abstract

Human alphaherpesviruses (αHHV) - herpes simplex virus type 1 (HSV-1), HSV-2, and varicella-zoster virus (VZV) - infect mucosal epithelial cells, establish a lifelong latent infection of sensory neurons, and reactivate intermittingly to cause recrudescent disease. Although chronic αHHV infections co-exist with brisk T-cell responses, T-cell immune suppression is associated with worsened recurrent infection. Induction of αHHV-specific T-cell immunity is complex and results in poly-specific CD4 and CD8 T-cell responses in peripheral blood. Specific T-cells are localized to ganglia during the chronic phase of HSV infection and to several infected areas during recurrences, and persist long after viral clearance. These recent advances hold promise in the design of new vaccine candidates.

Figure 1

HSV-specific CD8 T-cells in PBMC of HSV-seropositive immunocompetent individuals. (A) Cells specific for amino acids 49–57 of HSV-2 gene UL49 and restricted by HLA B*0702 can represent up to 3.09% of circulating CD8 T-cells. (B) CD8 T-cells specific for amino acids 90–99 of HSV-1 gene UL48, restricted by HLA A*0101, over-express CLA (red histogram) compared to the remaining CD8 T-cells (grey histogram).

Figure 2

Clusters of CD4 and CD8 T-cells surround HSV-1 LAT-positive neurons in human TG. (A, B) Consecutive TG sections were stained for HSV-1 LAT by in situ hybdrization (A) and CD3 by immunohistochemistry (B), showing that T-cell clusters surround HSV-1 LAT+ neurons. Arrows indicate LAT+ neurons. (C) Human TG immunofluorescently stained for CD4 (red) and CD8 (green, showing that ganglionic T-cell clusters are composed of both CD4 and CD8 T-cells. Dashed lines indicate neurons. Nuclei were counterstained with 4’,6-diamino-2-phenylindole. (D–F) Consecutive TG sections were stained for CD3 (D), CD200R (E) and CD200 (F) by immunohistochemistry. Ganglion-infiltrating T-cells express CD200R, whereas neuron-interacting satellite glial cells express its ligand CD200. (A, B, D–F) Sections were developed with 5-bromo-4-chloro-3-indolyl-phosphate (LAT; black color) and 3-amino-9-ethylcarbazole chromogen (CD3, CD69, CD200R and CD200; red color); nuclei were counterstained with hematoxylin. Magnification: (A, B) 100X, (C) 400X, (D–F) 200X.