Herpes Simplex Virus Protein Targets for CD4 and CD8 Lymphocyte Cytotoxicity in Cultured Epidermal Keratinocytes Treated with Interferon-γ

Mikloška, Zorka; Kesson, Alison; Penfold, Mark E.T.; Cunningham, Anthony L.

doi:10.1093/infdis/173.1.7

Cited by 76 publications

(105 citation statements)

References 52 publications

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“…The fact that CH responses in IFN-␥ receptor-deficient mice are only partially affected indicates a nonessential role for IFN-␥ in these immune responses (50). In contrast to our results, other studies indicated a higher lytic activity of herpes virus-specific CD4 ϩ T cells compared with CD8 ϩ lymphocytes against virus-infected keratinocytes (51). This finding could be the consequence of reduced MHC class I expression on keratinocytes infected with the herpes virus.…”

Section: Discussioncontrasting

confidence: 97%

Disparate Cytotoxic Activity of Nickel-Specific CD8+ and CD4+ T Cell Subsets Against Keratinocytes

Traidl

Sebastiani

Albanesi

et al. 2000

The Journal of Immunology

138

115

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Allergic contact dermatitis (ACD) is the result of an exaggerated immune reaction to haptens mediated by skin-homing T cells, but the effector mechanisms responsible for the tissue damage are poorly understood. Here we studied the capacity of distinct subsets of hapten-specific T cells to induce apoptosis in autologous keratinocytes. Skin- and blood-derived nickel-specific CD8+ T cytotoxic 1 (Tc1) and Tc2 clones as well as CD4+ Th1 and Th2 expressed the cutaneous lymphocyte-associated Ag and exhibited strong MHC-restricted cytotoxicity against nickel-coupled B lymphoblasts, as detected by the [3H]TdR release assay. Both Tc1 and Tc2 clones, but not CD4+ T cells, displayed a significant cytotoxic activity against resting nickel-modified keratinocytes. Following IFN-γ treatment, keratinocytes expressed MHC class II and ICAM-1 and became susceptible to Th1-mediated, but not Th2-mediated, cytotoxicity. The molecules of the two major cytotoxic pathways, Fas ligand (FasL) and perforin, were expressed by Tc1, Tc2, and Th1 cells, whereas Th2 cells expressed only FasL. Experiments performed in the presence of specific inhibitors of the perforin (concanamycin A) and FasL (brefeldin A) pathway indicated that perforin-mediated killing dominated in Tc1 and Tc2, and FasL-mediated cytotoxicity prevailed in Th2 clones, with a more heterogeneous behavior in the case of Th1 cells. Finally, perforin mRNA was expressed in ACD lesional skin, as assessed by RT-PCR analysis. In aggregate, our results indicate that keratinocytes can be target of multiple hapten-specific CTL responses, that may have distinct roles in the epidermal injury during ACD.

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Section: Discussioncontrasting

confidence: 97%

Disparate Cytotoxic Activity of Nickel-Specific CD8+ and CD4+ T Cell Subsets Against Keratinocytes

Traidl

Sebastiani

Albanesi

et al. 2000

The Journal of Immunology

138

115

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“…This is consistent with a previous study [2] and suggests that the CD8 + T cells are induced to secrete cytokine by peptide-loaded HLA class I on keratinocytes but only become cytotoxic when LFA-1 is engaged by ICAM-1 on the keratinocytes. Cytotoxic T cell lysis of keratinocytes is probably important in the control of cutaneous viral infections such as herpes simplex [30,31] and other inflammatory skin diseases associated with keratinocyte death such as lichen planus.…”

Section: Discussionmentioning

confidence: 99%

Human keratinocyte induction of rapid effector function in antigen‐specific memory CD4⁺ and CD8⁺ T cells

et al. 2007

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The ability of human keratinocytes to present antigen to T cells is controversial and, indeed, it has been suggested that keratinocytes may promote T cell hyporesponsiveness. Furthermore, it is unclear whether keratinocytes can process antigen prior to MHC class I and class II presentation. We tested the ability of keratinocytes to induce functional responses in epitope-specific CD4 + and CD8 + memory T cells using peptides, protein and recombinant expression vectors as sources of antigen. Keratinocytes were able to efficiently process and present protein antigen to CD4 + T cells, resulting in cytokine secretion (Th1 and Th2). This interaction was dependent on keratinocyte expression of HLA class II and ICAM-1, which could be induced by IFN-c. In addition, keratinocytes could present virally encoded or exogenous peptide to CD8 + T cells, resulting in T cell cytokine production and target cell lysis. Finally, T cell lines grown using keratinocytes as stimulators showed no loss of function. These findings demonstrate that keratinocytes are able to efficiently process and present antigen to CD4 + and CD8 + memory T cells and induce functional responses. The findings have broad implications for the pathogenesis of cutaneous disease and for transcutaneous drug or vaccine delivery.

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“…The two published epitopes are type-common peptides within glycoproteins B and D (10,15). At the nonclonal level, experiments using restimulation of PBMC, drug blocks, and vaccinia recombinants show that HSV-1 ICP4, ICP27, ICP0, all immediate early proteins, HSV-1 early protein ICP6, and possibly other true early proteins may be targets of human CTL (18,63,64). HSV-1 early protein thymidine kinase (tk) is recognized by CD8 clones from PBMC of subjects treated with tk-transfected autologous cells, but this is likely a primary immune response (65).…”

Section: Discussionmentioning

confidence: 99%

CD8 CTL from Genital Herpes Simplex Lesions: Recognition of Viral Tegument and Immediate Early Proteins and Lysis of Infected Cutaneous Cells

Koelle

Chen

Gavin

et al. 2001

The Journal of Immunology

116

173

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HSV-2 causes chronic infections. CD8 CTL may play several protective roles, and stimulation of a CD8 response is a rational element of vaccine design for this pathogen. The viral Ags recognized by CD8 T cells are largely unknown. It has been hypothesized that HSV inhibition of TAP may favor recognition of virion input proteins or viral immediate early proteins. We tested this prediction using HSV-specific CD8 CTL clones obtained from genital HSV-2 lesions. Drug and replication block experiments were consistent with specificity for the above-named classes of viral proteins. Fine specificity was determined by expression cloning using molecular libraries of viral DNA, and peptide epitopes recognized at nanomolar concentrations were identified. Three of four clones recognized the viral tegument proteins encoded by genes UL47 and UL49. These proteins are transferred into the cytoplasm on virus entry. Processing of the tegument Ag-derived epitopes was TAP dependent. The tegument-specific CTL were able to lyse HLA class I-appropriate fibroblasts after short times of infection. Lysis of keratinocytes required longer infection and pretreatment with IFN-γ. Another clone recognized an immediate early protein, ICP0. Lymphocytes specific for these lesion-defined epitopes could be reactivated from the PBMC of additional subjects. These data are consistent with an influence of HSV immune evasion genes upon the selection of proteins recognized by CD8 CTL in lesions. Tegument proteins, identified for the first time as Ags recognized by HSV-specific CD8 CTL, are rational candidate vaccine compounds.

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Herpes Simplex Virus Protein Targets for CD4 and CD8 Lymphocyte Cytotoxicity in Cultured Epidermal Keratinocytes Treated with Interferon-γ

Cited by 76 publications

References 52 publications

Disparate Cytotoxic Activity of Nickel-Specific CD8+ and CD4+ T Cell Subsets Against Keratinocytes

Disparate Cytotoxic Activity of Nickel-Specific CD8+ and CD4+ T Cell Subsets Against Keratinocytes

Human keratinocyte induction of rapid effector function in antigen‐specific memory CD4⁺ and CD8⁺ T cells

CD8 CTL from Genital Herpes Simplex Lesions: Recognition of Viral Tegument and Immediate Early Proteins and Lysis of Infected Cutaneous Cells

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Herpes Simplex Virus Protein Targets for CD4 and CD8 Lymphocyte Cytotoxicity in Cultured Epidermal Keratinocytes Treated with Interferon-γ

Cited by 76 publications

References 52 publications

Disparate Cytotoxic Activity of Nickel-Specific CD8+ and CD4+ T Cell Subsets Against Keratinocytes

Disparate Cytotoxic Activity of Nickel-Specific CD8+ and CD4+ T Cell Subsets Against Keratinocytes

Human keratinocyte induction of rapid effector function in antigen‐specific memory CD4+ and CD8+ T cells

CD8 CTL from Genital Herpes Simplex Lesions: Recognition of Viral Tegument and Immediate Early Proteins and Lysis of Infected Cutaneous Cells

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Human keratinocyte induction of rapid effector function in antigen‐specific memory CD4⁺ and CD8⁺ T cells