Expression of Granzyme B by Cytotoxic T Lymphocytes in the Lymph Nodes of HIV-infected Patients

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Abstract
During HIV infection the architecture of secondary lymphoid tissues is severely disrupted. In particular the germinal centers, which play a key role in the orchestration of the secondary immune response, undergo gross phenotypic alterations, leading to a complete destruction of the germinal center microenvironment. The precise mechanisms responsible for the lymphoid tissue destruction in HIV infection are still unknown. However, the large influx of CD8+ T lymphocytes suggests an important role for T cell-mediated cytotoxicity. To establish whether the infiltrating CD8+ T lymphocytes are killing competent, we investigated the expression of granzyme B, which is known to be present in the cytotoxic granules of NK cells and "activated" CTLs with cytolytic potential. We observed a 20-fold increase in the percentage of granzyme B-expressing CD8+ T cells in both the germinal center and the interfollicular areas in HIV patients relative to HIV-negative controls. This increase was present in patients with early-stage disease (i.e., absolute CD4+ T cell count > 500/μl) as well as in patients with intermediate and late-stage disease. Thus, from relatively early stages of HIV infection onward large numbers of killing competent T lymphocytes are present in the lymphoid tissues, a finding that supports the notion that CTL act as mediators of destruction of immune function during HIV infection.