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T cell response kinetics determines neuroinfection outcomes during murine HSV infection
Aisha G. Lee, … , Wayne M. Yokoyama, Haina Shin
Aisha G. Lee, … , Wayne M. Yokoyama, Haina Shin
Published March 12, 2020
Citation Information: JCI Insight. 2020;5(5):e134258. https://doi.org/10.1172/jci.insight.134258.
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Research Article Immunology Infectious disease

T cell response kinetics determines neuroinfection outcomes during murine HSV infection

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Abstract

Herpes simplex virus-2 (HSV-2) and HSV-1 both can cause genital herpes, a chronic infection that establishes a latent reservoir in the nervous system. Clinically, the recurrence frequency of HSV-1 genital herpes is considerably less than HSV-2 genital herpes, which correlates with reduced neuronal infection. The factors dictating the disparate outcomes of HSV-1 and HSV-2 genital herpes are unclear. In this study, we show that vaginal infection of mice with HSV-1 leads to the rapid appearance of mature DCs in the draining lymph node, which is dependent on an early burst of NK cell–mediated IFN-γ production in the vagina that occurs after HSV-1 infection but not HSV-2 infection. Rapid DC maturation after HSV-1 infection, but not HSV-2 infection, correlates with the accelerated generation of a neuroprotective T cell response and early accumulation of IFN-γ–producing T cells at the site of infection. Depletion of T cells or loss of IFN-γ receptor (IFN-γR) expression in sensory neurons both lead to a marked loss of neuroprotection only during HSV-1, recapitulating a prominent feature of HSV-2 infection. Our experiments reveal key differences in host control of neuronal HSV-1 and HSV-2 infection after genital exposure of mice, and they define parameters of a successful immune response against genital herpes.

Authors

Aisha G. Lee, Jason M. Scott, Maria Rita Fabbrizi, Xiaoping Jiang, Dorothy K. Sojka, Mark J. Miller, Megan T. Baldridge, Wayne M. Yokoyama, Haina Shin

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Figure 5

Rapid T cell activation occurs after vaginal HSV-1 infection.

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Rapid T cell activation occurs after vaginal HSV-1 infection.
Infections...
Infections were performed as described in Figure 2. (A) Total number of CD4+ T cells (left graph) and CD8+ T cells (right graph) at 2 d.p.i. in the dLN. (B) Plots show expression of CD69 on CD4+ (top) and CD8+ (bottom) T cells after HSV-1 (left) or HSV-2 (right) infection. Numbers indicate percentage of CD4+ or CD8+ T cells expressing CD69. Left graphs show frequency of CD69 expression in CD4+ (top) or CD8+ (bottom) T cells. Right graphs show number of CD69+CD4+ (top) or CD69+CD8+ (bottom) T cells. All data area at 2 d.p.i. in the dLN. (C–D) A total of 1 × 106 CFSE-labeled, CD45.1+ gBT-I CD8+ T cells were adoptively transferred to congenic naive recipients 1 day before HSV-1 or HSV-2 infection. (C) Plot is gated on total CD8+ T cells and shows CFSE dilution of gBT-I cells at 3 d.p.i. in the dLN. Histogram shows an overlay of gBT-I cells after HSV-1 (black) or HSV-2 (red) infection. Left graph shows percentage of CFSE-undivided (CFSE-undiluted) gBT-I cells. Right graph shows percentage of CFSE-divided (CFSE-diluted) gBT-I cells. (D) Plots are gated on gBT-I CD8+ T cells from the dLN and show expression of T-bet (top) and granzyme B (bottom) 3 days after HSV-1 infection. Boxes are drawn around divided gBT-I cells. Histograms show T-bet and granzyme B expression in divided gBT-I cells after HSV-1 (black) or HSV-2 (red) infection. MFI of T-bet expression (top graph) or granzyme B expression in the divided gBT-I population (bottom graph) is shown. Data in A and B are pooled from 3 independent experiments (HSV-1, n = 13; HSV-2, n = 12; mock, n = 7). Data in C and D are pooled from 2 independent experiments (HSV-1, n = 9; HSV-2, n = 10). Horizontal bars show mean, and all error bars show ± SD. Statistical significance in A and B was measured by 1-way ANOVA with Tukey’s multiple comparisons test. Statistical significance in A and B was measured by 2-tailed Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.005, ****P < 0.001.

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