Perforin is not co-expressed with granzyme A within cytotoxic granules in CD8 T-Lymphocytes present in lymphoid tissue during chronic HIV infection
| Autor: | Bruce K. Patterson, Alan L. Landay, Anders Sönnerborg, Uccini S, Thomas E. Fehniger, Homira Behbahani, Judy Lieberman, Elizabeth Connick, Karin Loré, Jan Andersson |
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| Rok vydání: | 1999 |
| Předmět: |
Pore Forming Cytotoxic Proteins
Lymphoid Tissue Palatine Tonsil Immunology HIV Infections CD8-Positive T-Lymphocytes Biology Cytoplasmic Granules Peripheral blood mononuclear cell Granzymes Image Processing Computer-Assisted Humans Immunology and Allergy Cytotoxic T cell Membrane Glycoproteins Perforin Serine Endopeptidases T lymphocyte Immunohistochemistry CD4 Lymphocyte Count Infectious Diseases Lymphatic system Granzyme HIV-1 biology.protein Granzyme A RNA Viral Lymph Nodes CD8 T-Lymphocytes Cytotoxic |
| Popis: | Background: Residual HIV-1-infected cells are poorly eliminated from lymphoid tissue (LT) reservoirs by effector cytotoxic T lymphocytes (eCTL) despite antiretroviral therapy. Perforin and granzyme A (grA) constitute major effector molecules within eCTL granules that induce apoptosis and lysis of virally infected cells. Objective: Expression of perforin and grA was studied at the single cell level in LT and blood from 16 patients infected with HIV-1 (stage A1-C) who were not taking antiretroviral therapy. Method: Immunohistochemical analysis by in situ imaging of cells from blood and LT. Results: Quantitative in situ imaging showed that perforin-expressing CD8 T cells comprised 0.3-1.5% of total cells within the LT from recent HIV-1 seroconverters, while grA was found in 2.1-7.2% of total cells. However, despite high-level grA upregulation (1.5-4.5% of total cells) compared with that in non-infected individuals (0.4-0.9%), perforin expression remained low (< 0.1% of total cells) (P < 0.02) in LT from patients with chronic HIV-1 infection (stage A2-C). This contrasted with findings in peripheral blood mononuclear cells (PBMC) from the same HIV-1 infected cohort where perforin was detected in 13-31% of all PBMC, which was 10- to 100-fold higher than in lymphoid tissue (P < 0.001); grA was found in 14-32% of total PBMC. Two-colour staining showed that granular expression of perforin and grA was restricted to CD8 T cells in over 90% of total cells in both LT and blood. Conclusions: These findings indicate that cytotoxic perforin expression is impaired at local sites of HIV replication within lymphoid tissue. Since perforin is required together with grA for granule-mediated cytolysis, the low perforin expression in the LT may limit the ability of eCTL to eliminate HIV-1 infected cells in lymphoid tissue. |
| Databáze: | OpenAIRE |
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