The fraction of perforin-expressing HIV-specific CD8 T cells is a marker for disease progression in HIV infection

Heintel, Tanja; Sester, Martina; Rodríguez, Maria M.; Krieg, Carsten; Sester, Urban; Wagner, Ralf; Pees, H. W.; Гартнер, Барбара; Maier, Reinhard; Meyerhans, Andreas

doi:10.1097/00002030-200207260-00006

Cited by 47 publications

(32 citation statements)

References 26 publications

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“…In HIV-1 infection, granule exocytosis, rather than Fas-mediated killing, is believed to be the major mechanism used by cytotoxic CD8 ϩ T cells to eliminate infected target cells (3,9,15). Several recent studies support a clinically relevant correlation between perforin expression, as measured by intracellular perforin in CD8 ϩ T cells, and immune control of HIV-1 infection (54,55).…”

Section: Discussionmentioning

confidence: 82%

Abundant Expression of Granzyme A, but Not Perforin, in Granules of CD8+ T Cells in GALT: Implications for Immune Control of HIV-1 Infection

Shacklett

Cox

Quigley

et al. 2004

The Journal of Immunology

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Because GALT is a major portal of entry for HIV-1 and reservoir for viral replication, we hypothesized that an ineffective cellular immune response in intestinal mucosa might partially explain the failure of immune control in AIDS. In this study, we demonstrate that the vast majority of CD8+ T cells in rectal tissue, including HIV-1-specific cells, fail to express the cytolytic protein, perforin. However, rectal CD8+ T cells do express granzyme A, and are also capable of releasing IFN-γ upon stimulation with cognate peptide. Confocal microscopy showed that granzyme A was located in intracellular granules in the absence of perforin. The majority of rectal CD8+ T cells exhibit an effector memory phenotype, expressing CD45RO but not CCR7. Quantitative real-time PCR analysis demonstrated that perforin RNA is expressed in rectal CD8+ T cells from healthy and HIV-1-positive individuals. In HIV-1-positive individuals, similar amounts of perforin RNA were detected in CD8+ T cells from rectal tissue and PBMC, despite a relative absence of perforin protein in rectal tissue. These findings demonstrate an important difference in perforin expression between CD8+ T cells in blood and mucosa. Furthermore, the relative absence of armed effector cells may serve to protect the integrity of rectal mucosa under normal conditions, but might also provide an early advantage to HIV-1 and other sexually transmitted viruses.

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Section: Discussionmentioning

confidence: 82%

Abundant Expression of Granzyme A, but Not Perforin, in Granules of CD8+ T Cells in GALT: Implications for Immune Control of HIV-1 Infection

Shacklett

Cox

Quigley

et al. 2004

The Journal of Immunology

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“…Indeed, CD8 T cells isolated from HIV + patients proliferate poorly to their cognate Ags and fail to express normal levels of perforin or IFN-g or demonstrate cytolytic activity in standard chromium release assays (65,(68)(69)(70)(71)(72). There is now abundant evidence demonstrating the negative effects of soluble Tat protein on lymphocyte function.…”

Section: Discussionmentioning

confidence: 99%

Soluble HIV Tat Protein Removes the IL-7 Receptor α-Chain from the Surface of Resting CD8 T Cells and Targets It for Degradation

Faller

Sugden

McVey

et al. 2010

The Journal of Immunology

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IL-7 signaling is essential to CD8 T cell development, activation, and homeostasis. We have previously shown decreased expression of the IL-7R α-chain (CD127) on CD8 T cells in HIV+ patients and that this downregulation is mediated at least in part by the HIV Tat protein. We show in this study that CD127 has a prolonged t1/2 in resting CD8 T cells and continuously recycles on and off the cell membrane. We also demonstrate soluble Tat protein significantly decreases the t1/2 of CD127. Soluble Tat is taken up from the medium and accumulates in CD8 T cells with a peak of 6 h. Once inside the cell, Tat exits the endosomes during their normal acidification and enters the cytosol. Tat then translocates to the inner leaflet of the cell membrane, where it binds directly to the cytoplasmic tail of CD127, inducing receptor aggregation and internalization through a process dependent on microtubules. Tat appears to then target CD127 for degradation via the proteasome. By removing CD127 from the cell surface, the HIV Tat protein is thus able to reduce IL-7 signaling and impair CD8 T cell proliferation and function.

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“…The incidence of IFN-γ + perforin high HIV-specific CD8 + T cells has been reported to correlate with HIV-1 disease progression (49,50). In addition, HIV long-term nonprogressors were associated with HIV-specific CD8 + T cells characterized by less-differentiated phenotype (CD45RO + /CD27 + /CD28 + ) and high proliferative capacity (51).…”

Section: Cd8 + T Cells In Trans By Apcsmentioning

confidence: 99%

Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells

Gattinoni

Klebanoff

Palmer

et al. 2005

Journal of Clinical Investigation

857

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T cell differentiation is a progressive process characterized by phenotypic and functional changes. By transferring tumor-specific CD8 + T cells into tumor-bearing mice at various stages of differentiation, we evaluated their efficacy for adoptive immunotherapy. We found that administration of naive and early effector T cells, in combination with active immunization and IL-2, resulted in the eradication of large, established tumors. Despite enhanced in vitro antitumor properties, more-differentiated effector T cells were less effective for in vivo tumor treatment. Several events may underlie this paradoxical phenomenon: (a) downregulation of lymphoid-homing and costimulatory molecules; (b) inability to produce IL-2 and access homeostatic cytokines; and (c) entry into a proapoptotic and replicative senescent state. While the progressive acquisition of terminal effector properties is characterized by pronounced in vitro tumor killing, in vivo T cell activation, proliferation, and survival are progressively impaired. These findings suggest that the current methodology for selecting T cells for transfer is inadequate and provide new criteria for the generation and the screening of optimal lymphocyte populations for adoptive immunotherapy. IntroductionAdoptive cell transfer therapy (ACT), the administration of ex vivoactivated and -expanded autologous tumor-reactive T cells, is currently one of the few immunotherapies that can induce objective clinical responses in significant numbers of patients with metastatic solid tumors (1-3). In a previous study, ACT after lymphodepleting conditioning caused objective responses in 46% of patients with metastatic melanoma refractory to other therapeutic modalities (4). We have now tripled the size of the original study (4), and the objective response rate exceeds 50%, and 11% of all patients treated are complete responders (5).There are several theoretical advantages to the use of ACT in treatment of cancer. Tumor-specific T cells can be activated and expanded to large numbers ex vivo, independently of the immunogenic properties of the tumor. Perhaps most important, the functional and phenotypic qualities of T cells can be selected prior to their adoptive transfer.Much progress has been made in the understanding of the properties of T cell subpopulations associated with states of T cell differentiation in mice and humans, especially those states that are related to the generation of memory T cells capable of protecting against viral challenge (6-9). However, little progress has been made in identifying the characteristics of cell states that are associated with the successful treatment of large, established tumors in mice or in humans.

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The fraction of perforin-expressing HIV-specific CD8 T cells is a marker for disease progression in HIV infection

Cited by 47 publications

References 26 publications

Abundant Expression of Granzyme A, but Not Perforin, in Granules of CD8+ T Cells in GALT: Implications for Immune Control of HIV-1 Infection

Abundant Expression of Granzyme A, but Not Perforin, in Granules of CD8+ T Cells in GALT: Implications for Immune Control of HIV-1 Infection

Soluble HIV Tat Protein Removes the IL-7 Receptor α-Chain from the Surface of Resting CD8 T Cells and Targets It for Degradation

Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells

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