Immunization with Different Viral Antigens Alters the Pattern of T Cell Exhaustion and Latency in Herpes Simplex Virus Type 1-Infected Mice

Abstract

We have shown previously that immunization with herpes simplex virus type 1 (HSV-1) glycoprotein K (gK) exacerbated corneal scarring (CS) in ocularly infected mice. In this study, we investigated whether higher levels of CS were correlated with higher levels of latency and T cell exhaustion in gK-immunized mice. BALB/c mice were vaccinated with baculovirus-expressed gK or gD or mock immunized. Twenty-one days after the third immunization, mice were ocularly infected with 2 ؋ 10 4 PFU/eye of virulent HSV-1 strain McKrae. On day 5 postinfection, virus replication in the eye was measured, and on day 30 postinfection, infiltration of the trigeminal ganglia (TG) by CD4, CD8, programmed death 1 (PD-1), and T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) was monitored by immunohistochemistry and quantitative real-time PCR (qRT-PCR). This study demonstrated that higher levels of CS were correlated with higher levels of latency, and this was associated with the presence of significantly higher numbers of CD4 ؉ PD-1 ؉ and CD8 ؉ PD-1 ؉ cells in the TG of the gK-immunized group than in both the gD-and mock-immunized groups. Levels of exhaustion associated with Tim-3 were the same among gK-and mock-vaccinated groups but higher than levels in the gD-vaccinated group. In this study, we have shown for the first time that both PD-1 and Tim-3 contribute to T cell exhaustion and an increase of latency in the TG of latently infected mice.

The Role of LAT in Increased CD8 + T Cell Exhaustion in Trigeminal Ganglia of Mice Latently Infected with Herpes Simplex Virus 1

“…This demonstrates an important role for both PD-1 and Tim-3 in relation to disease progression and pathology caused by T cells. This increased expression of exhaustion markers is also in line with a recent study in which we have shown that the level of Tim-3/PD-1 expression on T cells can be altered by immunization (4). In addition to PD-1 and Tim-3, it was recently shown that the absence of IL-21 or IL-21 receptor also contributed to T cell exhaustion (13,20,82).…”

Adaptive and Innate Transforming Growth Factor β Signaling Impact Herpes Simplex Virus 1 Latency and Reactivation

“…More recently, we demonstrated that HSV-1 subclinical reactivation increases T cell exhaustion in the TG of infected mice (3). We have also shown that T cell exhaustion can be altered by immunization using different HSV-1-expressed glycoproteins (5). TGF-␤ is one of the most potent immunosuppressive cytokines and acts as a master regulator of immune responses (39).…”

“…The custom-made primer and probe sets for LAT were forward primer 5Ј-GGGTGGGCTCGTGTTACA G-3Ј, reverse primer 5Ј-GGACGGGTAAGTAACAGAGTCTCTA-3Ј, and probe 5Ј-FAM-ACACCAGCCCGTTCTTT-3Ј, with an amplicon length of 81 bp, corresponding to LAT nucleotides (nt) 119553 to 119634. Quantitative realtime PCR (qRT-PCR) was performed using an ABI PRISM 7900HT sequence detection system (Applied Biosystems, Foster City, CA) in 384-well plates as we described previously (4,5). GAPDH (glyceraldehyde 3-phosphate dehydrogenase) RNA was used for the normalization of transcripts.…”

“…In contrast to lytic infection, during latency the latency-associated transcript (LAT) RNA species is the only gene product that is consistently detected in abundance after HSV-1 infection (16,57,63,70). In general, the level of LAT expression directly correlates with the incidence of recurrence and subsequent induction of eye disease (4,5,44,47). To determine if the absence of TGF-␤ signaling altered latency, LAT expression was measured in TG from the three groups of mice described above on day 30 post-ocular infection.…”

Galectin-9 Protein Is Up-regulated in Astrocytes by Tumor Necrosis Factor and Promotes Encephalitogenic T-cell Apoptosis

“…Recent evidence also points to a role for Gal-9 in regulating T-cell responses directly by inducing a state of exhaustion (52)(53)(54)(55) or indirectly by promoting the polarization of regulatory T-cells (21, 56 -58). To date the immunoregulatory capacity of glialderived Gal-9 has not been elucidated and is the subject of ongoing investigation.…”