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Functional and Phenotypic Characterization of CD57⁺CD4⁺ T Cells and Their Association with HIV-1-Induced T Cell Dysfunction¹

Department of Medicine, University of Colorado Health Sciences Center, Denver, CO 80262

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--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- 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.

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