Role of keratinocytes in human recurrent herpetic lesions. Ability to present herpes simplex virus antigen and act as targets for T lymphocyte cytotoxicity in vitro.

Abstract

In human recurrent herpetic lesions epidermal keratinocytes are induced to express HLA class II (DR) antigens. Keratinocytes derived from human split skin and cultured in vitro were induced to express HLA-DR but not -DQ antigens with IFN gamma preparations. These stimulated keratinocytes presented herpes simplex antigen directly to autologous blood-derived T lymphocytes in four of four subjects (stimulation indices: 1.5-2.7), suggesting that keratinocytes may have an accessory herpes simplex virus (HSV) antigen-presenting role in addition to the Langerhans cells and macrophages in herpetic skin lesions. Blood mononuclear cells from eight herpes simplex seropositive subjects which were activated in vitro by HSV antigen for 6 d showed cytotoxicity specific for HSV in infected autologous keratinocytes. This was significantly increased by prestimulation with IFN gamma (51-56% to 83-85%). In four of eight patients some cytotoxicity also occurred against uninfected, IFN gamma-stimulated keratinocytes. Lymphocyte subset analysis showed that cytotoxicity against HSV-infected, IFN gamma-stimulated keratinocyte targets was mediated by both CD3+ T lymphocytes and Leu llb+ natural killer cells. T lymphocyte cytotoxicity was mediated by both CD4+ and CD8+ T lymphocytes, suggesting a cytotoxic role for the activated CD4+ lymphocytes that initially predominate in herpetic lesions.

Monophosphoryl Lipid A and QS21 Increase CD8 T Lymphocyte Cytotoxicity to Herpes Simplex Virus-2 Infected Cell Proteins 4 and 27 Through IFN-γ and IL-12 Production

“…We also used negative selection for CD8 T cells in view of the potential inhibitory effects of anti-CD8 mAbs on CD8 lymphocytes. This method previously has been shown to provide excellent results for subset depletion without functional impairment (14,15). NK cells were also concurrently depleted, thus ensuring that the results of the assay were only from CD8 CTLs.…”

“…Using IFN-␥-pretreated HSV-infected human ECs as targets for autologous CTLs in vitro, we studied the magnitude and specificity of CD4 and CD8 T lymphocyte cytotoxicity for HSV target proteins (8,14). Treatment of IFN-␥-pretreated HSV-infected target cells with the DNA polymerase inhibitor phosphonoacetic acid was used to compare targets expressing only nonstructural immediate early (IE)/early (E) proteins with those expressing all HSV proteins.…”

Immune responses to replication-defective HSV-1 type vectors within the CNS: implications for gene therapy

“…It is important to note that anti-HSV MHC Class II T cells have been reported in a majority of infected individuals, but their role in controlling HSV-1 infections is not fully elucidated. 22 Latency plays an indirect role in immune evasion. During this phase of the life cycle, low-level transcription of a restricted number of viral sequences called the 'latency-associated transcripts' (LATs) occurs.…”

Interleukin-1 alpha gene-transcription in murine keratinocytes is inhibited by HSV-1 infection

“…Moreover, IL-1 provides signals for growth and differentiation of immune cells [13,17]. A crucial role for keratinocytes in the interaction between the skin and the immune system is suggested by the fact that keratinocytes can present HSV-l-antigen to T-cells [10], and that keratinocytes are capable of both transcribing and producing IL-1 [3,4,7,24].…”