A number of studies have shown that TNF-related apoptosis-inducing ligand (TRAIL) levels are elevated in HIV infection, suggesting a possible role in pathogenesis. An interesting new paper now implicates CD8 T cells as contributing to TRAIL production in people with AIDS. The researchers, led by Stefanie Kuerten, note that TRAIL production by CD8 T cells has been observed in murine studies in which CD8 T cell responses are generated in the absence of CD4 T cell help. These reports led them to develop a novel ELISpot assay for antigen-specific TRAIL production in order to assess whether the murine findings were echoed in HIV infection, where CD4 T cell help is compromised.
Their results show that TRAIL production by HIV-specific CD8 T cells increases as CD4 counts fall; in their small cohort of individuals with HIV infection, TRAIL production was only detectable when peripheral blood CD4 T cell counts fell below 200. The researchers also found that TRAIL production increased as the capacity of the CD8 T cells to produce interferon-gamma was lost. The phenomenon appeared restricted to CD8 T cells primed in the absence of CD4 T cell help, as TRAIL production by CD8 T cells specific for EBV, CMV and flu was not observed. The authors note that future studies should investigate whether new CD8 T cell responses to antigens encountered subsequent to CD4 decline also show evidence of TRAIL production, as these data would predict. They also speculate that TRAIL production by CD8 T cells might exacerbate CD4 T cell depletion by inducing apoptosis (a known function of TRAIL).
PDF full text: http://www.liebertonline.com/doi/pdfplus/10.1089/aid.2008.0062
AIDS Res Hum Retroviruses. 2008 Aug 26. [Epub ahead of print]
The TRAIL of Helpless CD8(+) T Cells in HIV Infection.
Kuerten S, Asaad RJ, Schoenberger SP, Angelov DN, Lehmann PV, Tary-Lehmann M.
Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106., Institut I fuer Anatomie, University of Cologne, Cologne, Germany.
Abstract Our understanding of how CD4(+) T cells can regulate CD8(+) T cell responses in HIV infection is still incomplete. Recent evidence obtained in mice suggests that CD4(+) T cell help is required for efficient CD8(+) T cell-mediated immunity in chronic infection: CD8(+) T cells primed in the absence of such help release the TNF-related apoptosis-inducing ligand TRAIL and undergo apoptosis. Using a novel ELISPOT assay, in the present study we show that CD8(+) T cells are also a source of the antigen-specific TRAIL response in HIV-infected patients with CD4(+) T cell counts below 200. In patients with CD4(+) T cell counts above 200 TRAIL was not detectable. Accordingly, antigens to which patients have likely been exposed when CD4(+) T cell levels were high (e.g., influenza, CMV, and EBV) did not induce TRAIL. Within the HIV-positive donor population with low CD4(+) T cell counts a dissociation of the interferon-gamma (IFN-gamma) and TRAIL response to different HIV peptide epitopes was detectable suggesting impaired immunity to antigens that triggered TRAIL in the absence of IFN-gamma. Our findings emphasize that "helpless" CD8(+) T cells, i.e., cells that have been primed in the absence of CD4(+) T cell help, may play a crucial role in HIV infection. A "helpless" phenotype may impair CD8(+) T cell control of HIV and other infections and possibly contribute to the depletion of CD4(+) T cells via apoptosis. Immunizations and infections in this "helpless" state might result in ineffective CD8(+) T cell responses.
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