Phenotypic and Functional Signatures of Herpes Simplex Virus-Specific Effector Memory CD73+CD45RAhighCCR7lowCD8+ TEMRA and CD73+CD45RAlowCCR7lowCD8+ TEM Cells Are Associated with Asymptomatic Ocular Herpes

doi:10.4049/jimmunol.1800725

Comparative Study

. 2018 Oct 15;201(8):2315-2330.

doi: 10.4049/jimmunol.1800725. Epub 2018 Sep 10.

Phenotypic and Functional Signatures of Herpes Simplex Virus-Specific Effector Memory CD73⁺CD45RA^highCCR7^lowCD8⁺ T_EMRA and CD73⁺CD45RA^lowCCR7^lowCD8⁺ T_EM Cells Are Associated with Asymptomatic Ocular Herpes

Ruchi Srivastava¹, Pierre-Grégoire Coulon¹, Soumyabrata Roy¹, Sravya Chilukuri¹, Sumit Garg¹, Lbachir BenMohamed^{2

3

4}

Affiliations

¹ Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, CA 92697.
² Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, CA 92697; Lbenmoha@uci.edu.
³ Department of Molecular Biology and Biochemistry, University of California Irvine, School of Medicine, Irvine, CA 92697; and.
⁴ Institute for Immunology, University of California Irvine, School of Medicine, Irvine, CA 92697.

PMID: 30201808
PMCID: PMC6195422
DOI: 10.4049/jimmunol.1800725

Comparative Study

Phenotypic and Functional Signatures of Herpes Simplex Virus-Specific Effector Memory CD73⁺CD45RA^highCCR7^lowCD8⁺ T_EMRA and CD73⁺CD45RA^lowCCR7^lowCD8⁺ T_EM Cells Are Associated with Asymptomatic Ocular Herpes

Ruchi Srivastava et al. J Immunol. 2018.

. 2018 Oct 15;201(8):2315-2330.

doi: 10.4049/jimmunol.1800725. Epub 2018 Sep 10.

Authors

Ruchi Srivastava¹, Pierre-Grégoire Coulon¹, Soumyabrata Roy¹, Sravya Chilukuri¹, Sumit Garg¹, Lbachir BenMohamed^{2

3

4}

Affiliations

¹ Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, CA 92697.
² Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine, School of Medicine, Irvine, CA 92697; Lbenmoha@uci.edu.
³ Department of Molecular Biology and Biochemistry, University of California Irvine, School of Medicine, Irvine, CA 92697; and.
⁴ Institute for Immunology, University of California Irvine, School of Medicine, Irvine, CA 92697.

PMID: 30201808
PMCID: PMC6195422
DOI: 10.4049/jimmunol.1800725

Abstract

HSV type 1 (HSV-1)-specific CD8⁺ T cells protect from herpes infection and disease. However, the nature of protective CD8⁺ T cells in HSV-1 seropositive healthy asymptomatic (ASYMP) individuals (with no history of clinical herpes disease) remains to be determined. In this study, we compared the phenotype and function of HSV-specific CD8⁺ T cells from HLA-A*02:01-positive ASYMP and symptomatic (SYMP) individuals (with a documented history of numerous episodes of recurrent ocular herpetic disease). We report that although SYMP and ASYMP individuals have similar frequencies of HSV-specific CD8⁺ T cells, the "naturally" protected ASYMP individuals have a significantly higher proportion of multifunctional HSV-specific effector memory CD8⁺ T cells (CD73⁺CD45RA^highCCR7^lowCD8⁺ effector memory RA (T_EMRA) and CD73⁺CD45RA^lowCCR7^lowCD8⁺ effector memory (T_EM) as compared with SYMP individuals. Similar to humans, HSV-1-infected ASYMP B6 mice had frequent multifunctional HSV-specific CD73⁺CD8⁺ T cells in the cornea, as compared with SYMP mice. Moreover, in contrast to wild type B6, CD73^-/- deficient mice infected ocularly with HSV-1 developed more recurrent corneal herpetic infection and disease. This was associated with less functional CD8⁺ T cells in the cornea and trigeminal ganglia, the sites of acute and latent infection. The phenotypic and functional characteristics of HSV-specific circulating and in situ CD73⁺CD8⁺ T cells, demonstrated in both ASYMP humans and mice, suggest a positive role for effector memory CD8⁺ T cells expressing the CD73 costimulatory molecule in the protection against ocular herpes infection and disease. These findings are important for the development of safe and effective T cell-based herpes immunotherapy.

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Conflict of interest statement

Conflict of Interest: The authors have declared that no conflicts of interest exist.

Figures

**Figure 1:. Frequent HSV-1 VP11/12_220–228 epitope-specific CD73⁺CD8⁺ memory T cells detected in ASYMP individuals compared to SYMP individuals:**
The frequency of CD73⁺CD8⁺ T cells specific to the VP_220–228 peptide/tetramer complex was analyzed in HLA-A*02:01 positive HSV-1 seropositive ASYMP and SYMP individuals. (A) Representative FACS data of the frequencies of CD73⁺CD8⁺ T cells, specific to VP11/12_220–228 epitope, detected in PBMCs from one HLA-A*02:01 positive HSV-1 seropositive ASYMP individual (*left two panels*) and one HLA-A*02:01 positive HSV-1 seropositive SYMP individual (*right two panels*). (B) Average frequencies of PBMC-derived CD8⁺ T cells, specific to VP11/12_220–228 epitope, detected from nine HLA-A*02:01 positive HSV-1 seropositive ASYMP individuals compared to nine HLA-A*02:01 positive HSV-seropositive SYMP individuals. The CD73 molecule expression level on CD8⁺ T cells specific to VP_220–228 epitope was analyzed in HLA-A*02:01 positive HSV-1 seropositive ASYMP and SYMP individuals. (C) Representative FACS data of the CD73 expression level on CD8⁺ T cells specific to VP_220–228 epitope detected from one HLA-A*02:01 positive HSV-1 seropositive ASYMP individual (*left panels*) and one HLA-A*02:01 positive HSV-1 seropositive SYMP individual (*right panels*). (D) Average CD73 expression level on CD8⁺ T cells, specific to VP11/12_220–228 epitope, detected from eight HLA-A*02:01 positive HSV-1 seropositive ASYMP individuals compared to six HLA-A*02:01 positive HSV-seropositive SYMP individuals. The frequency of A2AR⁺CD8⁺ T cells specific to VP_220–228 epitopes complex was analyzed in ASYMP and SYMP individuals. (E) Representative FACS data of the frequencies of A2AR⁺CD8⁺ T cells detected from one ASYMP (*left panel*) and one SYMP individual (*right panel*). (F) Average frequencies of A2AR⁺CD8⁺ T cells from nine ASYMP compared to nine SYMP individuals. The results are representative of two independent experiments in each individual. The indicated P values, calculated using unpaired t test, show statistical significance between SYMP and ASYMP individuals.

Figure 2.. Frequent HSV-1 VP11/12_220–228 epitope-specific CD8⁺ T cells with effector memory phenotype (CD73⁺CD8⁺ T_EMRA and CD73⁺CD8⁺ T_EM cells) detected in ASYMP individuals compared to SYMP individuals:
The CD8⁺ T cells specific to VP11/12_220–228 peptide/tetramer representing shown in Fig. 1 were analyzed in terms of T_NAIVE, T_CM, T_EMRA and T_EM phenotypes. Representative FACS data of the frequencies of (A) CD45RA^highCCR7^highCD8⁺ T_NAIVE cells, (C) CD45RA^lowCCR7^highCD8⁺ T_CM cells, (E) CD45RA^highCCR7^lowCD8⁺ T_EMRA cells, and (G) and CD45RA^lowCCR7^lowCD8⁺ T_EM cells detected in one ASYMP individual and one SYMP individual. Representative FACS data of the frequencies of (B) CD45RA^highCCR7^highCD8⁺ T_NAIVE cells, (D) CD45RA^lowCCR7^highCD8⁺ T_CM cells, (F) CD45RA^highCCR7^lowCD8⁺ T_EMRA cells and (H) CD45RA^lowCCR7^lowCD8⁺ T_EM cells detected from 10 ASYMP and 10 SYMP individuals. The results are representative of two independent experiments in each individual. The indicated P values, calculated using unpaired t test, show statistical significance between SYMP and ASYMP individuals.

**Figure 3.. Frequent HSV-1 VP11/12_220–228 epitope-specific CD73⁺CD8⁺ polyfunctional T cells detected in symptomatic individuals:**
(A) VP11/12_220–228 epitope-primed CD8⁺ T cells from ASYMP individuals were divided into CD73⁺CD8⁺ T cells and CD73⁻CD8⁺ T cells and their functions compared. (B) FACS was used to determine the expression level of CD107^a/b on tetramer gated CD8⁺ T cells specific to VP11/12_220–228 epitope, as described in the *Materials and Methods section*. VP11/12_220–228 epitope-specific CD73⁺CD8⁺ T cells express high levels of CD107^a/b cytotoxic degranulation compared to CD73⁻CD8⁺ T cells. The numbers on the top of each histogram represent the mean fluorescent intensity (MFI) depicting the expression level of CD107^a/b molecules. Numbers in bold represent mean fluorescent intensity (MFI) on CD73⁺CD8⁺ T cells from ASYMP individual. Representative FACS data (C) and average percentage (D) of VP11/12_220–228 epitope-specific CD107a/b⁺CD73⁺CD8⁺ T cells versus CD107a/b⁺CD73⁻CD8⁺ T cells. (E) Level of CD107^a/b molecules expression on VP11/12_220–228 epitope-specific CD8⁺ T cells following co-stimulation with (i) mAbs anti-CD3 alone, (ii) mAbs anti-CD3 + mAbs anti-CD28 (*iii*) anti-CD3 + mAbs anti-CD73. Representative FACS data (F) and average percentage (G) of VP11/12_220–228 epitope-specific IFN-γ⁺CD73⁺CD8⁺ T cells versus IFN-γ⁺CD73⁻CD8⁺ T cells are shown. (H) IFN-γ expression level on VP11/12_220–228 epitope-specific CD8⁺ T cells following co-stimulation on with (i) mAbs anti-CD3 alone, (ii) mAbs anti-CD3 + mAbs anti-CD28 (*iii*) anti-CD3 + mAbs anti-CD73. Representative FACS data (I) and average percentages (J) of VP11/12_220–228 epitope-specific TNF-α⁺CD73⁺CD8⁺ T cells versus TNF-α⁺CD73⁻CD8⁺ T cells are shown. (K) TNF-α expression levels on VP11/12_220–228 epitope-specific CD8⁺ T cells following co-stimulation on with (i) mAbs anti-CD3 alone, (ii) mAbs anti-CD3 + mAbs anti-CD28 (*iii*) anti-CD3 + mAbs anti-CD73. The average frequencies of CD8⁺ T cells from 10 HLA-A*02:01-positive ASYMP and 10 SYMP individuals in response to stimulation with the VP11/12_220–228 peptide are shown. The results are representative of two independent experiments in each individual. The indicated P values, calculated using one-way ANOVA Test, show statistical significance between SYMP and ASYMP individuals.

**Figure 4.. HSV-1 VP11/12_220–228 epitope-specific CD73⁺CD8⁺ T cells are more functional:**
Correlation of VP11/12_220–228 epitope-specific CD73⁺CD8⁺ T cells percentage in PBMC with (A) expression of CD107^a/b cytotoxic degranulation molecules, and production of (B) IFN-γ and (C) TNF-α. Correlation of VP11/12_220–228 epitope-specific CD73⁻CD8⁺ T cells percentage in PBMC with (D) expression of CD107^a/b cytotoxic degranulation molecules, and production of (E) IFN-γ and (F) TNF-α. The nominal P values show statistical significance between the percentage of VP11/12_220–228 epitope-specific CD8⁺ T cells and production of IFN-γ function.

**Figure 5.. HSV-1 VP11/12_220–228 epitope-specific CD73⁻CD8⁺ T cells are dysfunctional (exhausted):**
VP11/12_220–228 epitope-specific CD8⁺ T cells from ASYMP and SYMP individuals were divided into CD73⁺CD8⁺ T cells and CD73⁻CD8⁺ T cells and their function compared. VP11/12_220–228 epitope-specific CD73⁻CD8⁺ T cells express high level of PD-1 marker of exhaustion compared to CD73⁺CD8⁺ T cells. FACS was used to determine the expression level of PD-1 on tetramer gated CD8⁺ T cells specific to VP11/12_220–228 epitope, as described in the *Materials & Methods* section. The numbers on the top of each histogram represent mean fluorescent intensity (MFI) depicting the expression level of PD-1 molecule. (A) Representative FACS data (B) average MFI (C) and average percentage of VP11/12_220–228 epitope-specific PD-1^highCD73⁺CD8⁺ T cells versus PD-1^highCD73⁻CD8⁺ T cells are shown. (D) An inverse correlation of VP11/12_220–228 epitope-specific CD73⁺CD8⁺ T cells percentage in PBMC with PD-1 expression in SYMP and ASYMP individuals. The results are representative of two independent experiments in each individual. The indicated P values, calculated using unpaired t test, show statistical significance between SYMP and ASYMP individuals.

**Figure 6.. Frequent functional gB_498–505 epitope-specific CD73⁺CD8⁺ T cells detected in the cornea and trigeminal ganglia of HSV-1 infected ASYMP B6 mice:**
(A and B) Kinetics of CD73 molecule expression in cornea- and trigeminal ganglia-derived CD8⁺ T cells. Flow cytometry of the frequency of gB_498–505 epitope specific CD73⁺CD8⁺ T cells in the cornea and trigeminal ganglia (TG) of B6 mice (n =10) following ocular infection with HSV-1 (McKrae, 2 × 10⁵ pfu/eye). (C) Representative FACS data (*left panel*) and average frequency (*right panel*) of the gB_498–505 epitope-specific CD73⁺CD8⁺ T cells in the cornea and trigeminal ganglia (TG) of ASYMP (n = 5) versus SYMP (n = 5) mice. (D) Representative FACS data (*left panel*) and average frequency (*right panel*) of the gB_498–505 epitope-specific IFN-γ⁺CD8⁺ T cells (E) and CD107⁺CD8⁺ T cells in the cornea and trigeminal ganglia (TG) of ASYMP (n = 5) versus SYMP (n = 5) mice. Data are representative of two independent experiments. The indicated P values, calculated using unpaired t test, show statistical significance between SYMP and ASYMP individuals.

Figure 7.. CD73^−/− deficient mice developed more corneal infection and severe herpetic disease associated with less functional HSV-specific CD8⁺ T cells in cornea and trigeminal ganglia compared to WT B6 mice:
(A) Schematic representation of the timeline of HSV-1 infection and UV-B induced recurrent disease in WT B6 mice and CD73^−/− deficient mice. A group of CD73^−/− deficient mice and WT mice (6–8 weeks old) were ocularly infected on day 0 with 2 × 10⁵ pfu of HSV-1 (strain McKrae) following scarification. After establishment of latency (35 days post-infection), reactivation of latent virus was induced following irradiation with UV-B. Tears were collected daily for six days post-UV-B and recurrent corneal disease was observed daily for eye disease for 25 days post UV-B exposure. (B) Presence of infectious virus in the tears of WT and CD73^−/− mice post UV-B treatment. Viral titer estimation detected in tear samples six days post UV-B irradiation expressed as mean of virus load. The data are expressed as mean of virus load (plaque forming units (pfu)/ml). (C) Recurrent corneal herpetic disease detected for up to 25 days following UV-B irradiation and scored on a scale of 0 to 4. (D) Representative slit lamp images of WT and CD73^−/− mice corneas. Mice were euthanized on day 60 post UV-B exposure and single cell suspensions from cornea and TG was obtained after collagenase treatment and stained for markers of CD8⁺ T cells, IFN-γ and CD107 and analyzed by immunostaining and FACS. Sections of the cornea (E) and TG (I) from WT and CD73^−/− mice were co-stained using Blue - DAPI (DNA stain), mAb specific to CD103-Red - Green - CD8 Infiltration. Single cell suspension from the cornea was obtained after collagenase treatment at 37⁰C for an hour and stained for markers of CD8⁺ T_RM cells, IFN-γ and CD107^a/b and analyzed by FACS. Representative FACS plot of the frequency of HSV-specific CD103⁺CD8⁺ T cells (F and J), IFN-γ⁺CD8⁺ T cells (G and K) and CD107^a/b+CD8⁺ T cells (H and L) detected in cornea and TG of WT and CD73^−/− deficient mice. The results are representative of two independent experiments. The indicated P values, calculated using an unpaired t test, show statistical significance between WT and CD73^−/− deficient mice.

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References

1. Dervillez X, Qureshi H, Chentoufi AA, Khan AA, Kritzer E, Yu DC, Diaz OR, Gottimukkala C, Kalantari M, Villacres MC, Scarfone VM, McKinney DM, Sidney J, Sette A, Nesburn AB, Wechsler SL, and BenMohamed L. 2013. Asymptomatic HLA-A*02:01-restricted epitopes from herpes simplex virus glycoprotein B preferentially recall polyfunctional CD8+ T cells from seropositive asymptomatic individuals and protect HLA transgenic mice against ocular herpes. J Immunol 191: 5124–5138. - PMC - PubMed
1. Chentoufi AA, Zhang X, Lamberth K, Dasgupta G, Bettahi I, Nguyen A, Wu M, Zhu X, Mohebbi A, Buus S, Wechsler SL, Nesburn AB, and BenMohamed L. 2008. HLA-A*0201-restricted CD8+ cytotoxic T lymphocyte epitopes identified from herpes simplex virus glycoprotein D. J Immunol 180: 426–437. - PubMed
1. Zhang X, Dervillez X, Chentoufi AA, Badakhshan T, Bettahi I, and BenMohamed L. 2012. Targeting the genital tract mucosa with a lipopeptide/recombinant adenovirus prime/boost vaccine induces potent and long-lasting CD8+ T cell immunity against herpes: importance of MyD88. J Immunol 189: 4496–4509. - PMC - PubMed
1. Samandary S, Kridane-Miledi H, Sandoval JS, Choudhury Z, Langa-Vives F, Spencer D, Chentoufi AA, Lemonnier FA, and BenMohamed L. 2014. Associations of HLA-A, HLA-B and HLA-C alleles frequency with prevalence of herpes simplex virus infections and diseases across global populations: implication for the development of an universal CD8+ T-cell epitope-based vaccine. Hum Immunol 75: 715–729. - PMC - PubMed
1. Kuo T, Wang C, Badakhshan T, Chilukuri S, and BenMohamed L. 2014. The Challenges and Opportunities for the Development of a T-Cell Epitope-Based Herpes Simplex Vaccine. Vaccine 34: 715–729. - PMC - PubMed

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[1] Dervillez X, Qureshi H, Chentoufi AA, Khan AA, Kritzer E, Yu DC, Diaz OR, Gottimukkala C, Kalantari M, Villacres MC, Scarfone VM, McKinney DM, Sidney J, Sette A, Nesburn AB, Wechsler SL, and BenMohamed L. 2013. Asymptomatic HLA-A*02:01-restricted epitopes from herpes simplex virus glycoprotein B preferentially recall polyfunctional CD8+ T cells from seropositive asymptomatic individuals and protect HLA transgenic mice against ocular herpes. J Immunol 191: 5124–5138. - PMC - PubMed

[2] Dervillez X, Qureshi H, Chentoufi AA, Khan AA, Kritzer E, Yu DC, Diaz OR, Gottimukkala C, Kalantari M, Villacres MC, Scarfone VM, McKinney DM, Sidney J, Sette A, Nesburn AB, Wechsler SL, and BenMohamed L. 2013. Asymptomatic HLA-A*02:01-restricted epitopes from herpes simplex virus glycoprotein B preferentially recall polyfunctional CD8+ T cells from seropositive asymptomatic individuals and protect HLA transgenic mice against ocular herpes. J Immunol 191: 5124–5138. - PMC - PubMed

[3] Chentoufi AA, Zhang X, Lamberth K, Dasgupta G, Bettahi I, Nguyen A, Wu M, Zhu X, Mohebbi A, Buus S, Wechsler SL, Nesburn AB, and BenMohamed L. 2008. HLA-A*0201-restricted CD8+ cytotoxic T lymphocyte epitopes identified from herpes simplex virus glycoprotein D. J Immunol 180: 426–437. - PubMed

[4] Chentoufi AA, Zhang X, Lamberth K, Dasgupta G, Bettahi I, Nguyen A, Wu M, Zhu X, Mohebbi A, Buus S, Wechsler SL, Nesburn AB, and BenMohamed L. 2008. HLA-A*0201-restricted CD8+ cytotoxic T lymphocyte epitopes identified from herpes simplex virus glycoprotein D. J Immunol 180: 426–437. - PubMed

[5] Zhang X, Dervillez X, Chentoufi AA, Badakhshan T, Bettahi I, and BenMohamed L. 2012. Targeting the genital tract mucosa with a lipopeptide/recombinant adenovirus prime/boost vaccine induces potent and long-lasting CD8+ T cell immunity against herpes: importance of MyD88. J Immunol 189: 4496–4509. - PMC - PubMed

[6] Zhang X, Dervillez X, Chentoufi AA, Badakhshan T, Bettahi I, and BenMohamed L. 2012. Targeting the genital tract mucosa with a lipopeptide/recombinant adenovirus prime/boost vaccine induces potent and long-lasting CD8+ T cell immunity against herpes: importance of MyD88. J Immunol 189: 4496–4509. - PMC - PubMed

[7] Samandary S, Kridane-Miledi H, Sandoval JS, Choudhury Z, Langa-Vives F, Spencer D, Chentoufi AA, Lemonnier FA, and BenMohamed L. 2014. Associations of HLA-A, HLA-B and HLA-C alleles frequency with prevalence of herpes simplex virus infections and diseases across global populations: implication for the development of an universal CD8+ T-cell epitope-based vaccine. Hum Immunol 75: 715–729. - PMC - PubMed

[8] Samandary S, Kridane-Miledi H, Sandoval JS, Choudhury Z, Langa-Vives F, Spencer D, Chentoufi AA, Lemonnier FA, and BenMohamed L. 2014. Associations of HLA-A, HLA-B and HLA-C alleles frequency with prevalence of herpes simplex virus infections and diseases across global populations: implication for the development of an universal CD8+ T-cell epitope-based vaccine. Hum Immunol 75: 715–729. - PMC - PubMed

[9] Kuo T, Wang C, Badakhshan T, Chilukuri S, and BenMohamed L. 2014. The Challenges and Opportunities for the Development of a T-Cell Epitope-Based Herpes Simplex Vaccine. Vaccine 34: 715–729. - PMC - PubMed

[10] Kuo T, Wang C, Badakhshan T, Chilukuri S, and BenMohamed L. 2014. The Challenges and Opportunities for the Development of a T-Cell Epitope-Based Herpes Simplex Vaccine. Vaccine 34: 715–729. - PMC - PubMed

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Phenotypic and Functional Signatures of Herpes Simplex Virus-Specific Effector Memory CD73⁺CD45RA^highCCR7^lowCD8⁺ T_EMRA and CD73⁺CD45RA^lowCCR7^lowCD8⁺ T_EM Cells Are Associated with Asymptomatic Ocular Herpes

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Phenotypic and Functional Signatures of Herpes Simplex Virus-Specific Effector Memory CD73⁺CD45RA^highCCR7^lowCD8⁺ T_EMRA and CD73⁺CD45RA^lowCCR7^lowCD8⁺ T_EM Cells Are Associated with Asymptomatic Ocular Herpes

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