Functional and Phenotypic Characterization of CD57+CD4+ T Cells and Their Association with HIV-1-Induced T Cell Dysfunction

Abstract

HIV-1 replication is associated with reduced or absent HIV-1-specific CD4+ T cell proliferation and skewing of HIV-1-specific CD4+ T cells toward an IFN-γ-producing, CCR7− phenotype. The CCR7− T cell population is heterogeneous and can be subdivided based on the expression of CD57. Although CD57 expression on CD8+ T cells is associated with proliferation incompetence and replicative senescence, less is known about the function of CD57-expressing CD4+ T cells. In this study, the frequency, phenotype, and function of CD57+CD4+ T cells were evaluated in 25 HIV-1-infected subjects and 10 seronegative controls. CD57+CD4+ T cells were found to be proliferation incompetent, even after strong mitogen stimulation. Percentages of CD4+ T cells that expressed CD57 were significantly higher in untreated HIV-1-infected subjects than in HIV-1-seronegative donors, and CD57 expression did not normalize in subjects receiving at least 6 mo of effective antiretroviral therapy. CD57 was predominately expressed on the CCR7− fraction of the CD4+ T cell compartment and accounted for the majority of cells in the CCR7−CD45RA+ population from untreated HIV-1-infected subjects. HIV-1-specific CD4+ T cells producing only IFN-γ had the highest expression of CD57, whereas few cells producing IL-2 alone expressed CD57. These findings further define a novel population of proliferation-incompetent CD4+ T cells that are generated in the presence of chronic Ag exposure. A better understanding of the generation and persistence of CD57+ T cells in HIV-1 infection could provide important insights into the immunopathogenesis of this disease.

Programmed Death 1 Expression on HIV-Specific CD4+ T Cells Is Driven by Viral Replication and Associated with T Cell Dysfunction

“…We have previously shown that HIV-specific CD4 ϩ T cells are skewed by viral replication toward an effector memory T (T Em ) cell 3 phenotype as identified by the loss of CCR7 and the acquisition of CD57 (1,2). HIV-specific CD4 ϩ T Em cells from subjects with chronic HIV infection proliferate poorly and lack the ability to secrete IL-2 (2-4).…”

“…Biexponential scaling was used in all dot plots. We examined the expression of PD-1 only on cytokine-producing cells with frequencies Ն0.04% to ensure an adequate number of events for a valid analysis as previously validated by our laboratory (1,2).…”

Up-Regulation of Programmed Death-1 Expression on Beryllium-Specific CD4+ T Cells in Chronic Beryllium Disease

“…Biexponential scaling was used in all dot plots. Because the frequency of beryllium-specific CD4 ϩ T cells in blood tends to be low, we only examined the expression of PD-1 on cytokine-producing cells with frequencies Ն0.04% to ensure an adequate number of events for analysis as previously described (31)(32)(33). The CFSE-blocking experiments were acquired using a FACSCalibur flow cytometer (BD Immunocytometry Systems), and CellQuest Pro software was used to analyze the data.…”

“…Proliferation assays were performed using PBMCs and BAL cells (2 ϫ 10 6 cells/well) labeled with 2.0 M CFSE (Molecular Probes) (31,32). The CFSE-labeled cells were cultured at 37°C for 5 days in a humidified 5% CO 2 atmosphere in RPMI 1640 supplemented with 10% heat-inactivated human serum, 20 mM HEPES, 1 mM sodium pyruvate, 100 U/ml penicillin, 100 g/ml streptomycin, and 2 mM L-glutamine (all from Invitrogen Life Technologies) with the addition of either medium, 10 g/ml platebound anti-CD3, or 100 M BeSO 4 .…”

γδ+ T Cells Involvement in Viral Immune Control of Chronic Human Herpesvirus 8 Infection

“…Significant increases in relative frequency of CD57 ϩ T cells have been reported in situations of persistent viral infection and chronic inflammation (41,42). Recently, CD57 expression on CD4 and CD8 lymphocytes was also associated with replicative senescence and terminal differentiation (31,32). It is commonly accepted that this is the result of chronic activation due to persistent Ag exposure.…”