Cutting Edge: Virus-Specific CD8+ T Cell Clones and the Maintenance of Replicative Function during a Persistent Viral Infection

Bannard, Oliver; Kraman, Matthew; Fearon, Douglas T.

doi:10.4049/jimmunol.1002537

Cited by 11 publications

(11 citation statements)

References 15 publications

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“…S7A). A small percentage of cells (~10%) in both CD27 + CD57 + and CD27 + CD57 − subsets expressed another marker for senescence and terminal differentiation, KLRG-1 (Data not shown) (15,47). To further examine the proliferative capacity of these cells, we stained the cultured TIL with Ki67 at the end of the 2-week culture period and found that both CD8 + CD27 + CD57 + and CD8 + CD27 + CD57 − subsets contained a significant frequency of Ki67 + cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Detection and Characterization of a Novel Subset of CD8+CD57+ T Cells in Metastatic Melanoma with an Incompletely Differentiated Phenotype

Liu

Chacon

et al. 2012

Clinical Cancer Research

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PURPOSE Tumor-specific T-cells are frequently induced naturally in melanoma patients and infiltrate tumors. It is enigmatic why these patients fail to experience tumor regression. Given that CD8+ T cells mediate antigen-specific killing of tumor cells, the focus of this study was to identify alterations in the differentiation of CD8+ residing at the tumor site, with emphasis on a population expressing CD57, a marker for terminal differentiation. EXPERIMENTAL DESIGN We performed flow cytometric analysis of CD8+ tumor-infiltrating lymphocytes (TIL) isolated from 44 resected melanoma metastases using known T-cell differentiation markers. For comparison, PBMC were isolated from matched melanoma patients. We sorted different CD8+ subsets found in TIL and determined their effector functions. In addition, we performed Vβ spectratyping of T-cell receptors to determine lineage relationship between the CD8+ TIL subsets. RESULTS The majority of CD8+ TIL were in the early effector-memory stage of differentiation. A significant population consisted of an oligoclonal subset of cells co-expressing early effector-memory markers and end-stage CTL marker, CD57, yet having low to absent perforin expression. These cells could be induced to proliferate, produce a high level of IFN-γ, and differentiate into CD27−CD57+, perforinhigh mature CTL in vitro. Addition of TGF-β1 prevented this further differentiation. CONCLUSIONS Our studies identified a novel subset of incompletely differentiated CD8+ CTL co-expressing early effector-memory and late CTL markers. This population resembles that found by in patients with uncontrolled chronic viral infections. TGF-β1, frequently produced by melanoma tumors, may be a key cytokine inhibiting the further maturation of this subset.

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Section: Resultsmentioning

confidence: 99%

Detection and Characterization of a Novel Subset of CD8+CD57+ T Cells in Metastatic Melanoma with an Incompletely Differentiated Phenotype

Liu

Chacon

et al. 2012

Clinical Cancer Research

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“…It is unclear how the antiviral T cell response is maintained long-term during persistent γ-herpesvirus infections. Using the mouse γHV68 infection model, it has been shown that virus-specific CD8 T cells proliferate rapidly during latency, yet the majority of antiviral CD8 T cells express markers of terminal differentiation and replicative senescence (5, 10, 35-37). In order to design rational therapeutic vaccine strategies that target epitope-specific CD8 T cell responses, it is important to determine how antiviral memory T cell is maintained long-term.…”

Section: Discussionmentioning

confidence: 99%

“…We have recently demonstrated that virus-specific naïve CD4 T cells can enter the immune response during γHV68 latency (39). However, another recent report has suggested that the CD8 T cell response to γHV68 is maintained mainly by the continuous turnover of activated T cells that were primed during acute infection (5). Importantly, that report did not rule out the possibility that naïve T cells could contribute to the ongoing antiviral T cell response, and did not examine epitope-specific T cell responses.…”

Section: Discussionmentioning

confidence: 99%

“…First, a subset of memory T cells that retains the capacity for self-renewal can replenish the memory pool as non-replicating memory T cells are eliminated. In this model, all of the memory T cells required for controlling the latent pathogen are derived from cells stimulated during the initial acute infection (4, 5). Alternatively, new naïve cells with specificity for viral epitopes can be recruited into the ongoing T cell response, supplying a population of cells to replace pre-existing memory cells.…”

Section: Introductionmentioning

confidence: 99%

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γ-Herpesvirus Reactivation Differentially Stimulates Epitope-Specific CD8 T Cell Responses

Freeman

Burkum

Jensen

et al. 2012

The Journal of Immunology

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The γ-herpesviruses are characterized by their ability to establish lifelong latency. Subsequent immune suppression leads to viral reactivation from latency and the onset of a variety of pathologies, including lymphoproliferative disease and cancers. CD8 T cells play a key role in preventing reactivation of latent virus. Therefore, to develop effective therapeutic immune strategies, it is essential to understand the maintenance of CD8 T cell responses during latency. Because the γ-herpesviruses are highly species-specific and mice cannot be infected with the human pathogens, EBV or Kaposi’s sarcoma-associated herpesvirus, we have used a natural rodent γ-herpesvirus experimental infection model, γ-herpesvirus-68. In this report, we show that during long-term latent infection, naive CD8 T cells are recruited into the ongoing immune response in an epitope-specific manner. When virus reactivation is induced in vivo, the recruitment of CD8 T cells for some, but not all, epitopes is enhanced. The variation in recruitment is not due to differences in epitope presentation. We also show that CD8 T cells that are newly stimulated during reactivation are functionally impaired compared with acutely stimulated cells in terms of cytokine production. Thus, our results demonstrate unexpected complexity in the response of CD8 T cells specific for different viral epitopes that were stimulated during acute infection, quiescent latency, and reactivation.

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“…That would be theoretically feasible if we knew how to generate selfrenewing memory T cells. While such memory T cells having stem cell-like selfrenewal potential exist in vivo, [8][9][10] we ignore how to generate them ex vivo. Current methods for ex vivo expansion of Ag-specific T cells yield poorly functional exhausted T cells that rapidly disappear after in vivo transfer.…”

Section: Claude Perreault Université De Montréalmentioning

confidence: 99%

CD9 phones home with a TEM of its own

Brown

Savona

2011

Blood

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Cutting Edge: Virus-Specific CD8+ T Cell Clones and the Maintenance of Replicative Function during a Persistent Viral Infection

Cited by 11 publications

References 15 publications

Detection and Characterization of a Novel Subset of CD8+CD57+ T Cells in Metastatic Melanoma with an Incompletely Differentiated Phenotype

Detection and Characterization of a Novel Subset of CD8+CD57+ T Cells in Metastatic Melanoma with an Incompletely Differentiated Phenotype

γ-Herpesvirus Reactivation Differentially Stimulates Epitope-Specific CD8 T Cell Responses

CD9 phones home with a TEM of its own

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