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Levels of CMV specific CD4 T cells are dynamic and correlate with CMV viremia after allogeneic stem cell transplantation.

Widmann T, Sester U, Gärtner BC, Schubert J, Pfreundschuh M, Köhler H, Sester M - PLoS ONE (2008)

Bottom Line: In contrast, CMV-peptide specific CD8 T cells did not show any association with viremia (p = 0.82).Interestingly, therapeutic dosages of cyclosporine A and corticosteroids led to a dose-dependent reduction of CMV-specific T-cell functions, indicating a causal link between intensified immunosuppressive treatment and CMV reactivation.In conclusion, levels of CMV-specific CD4 T cells inversely correlate with reactivation episodes and may represent a valuable measure to individually guide antiviral therapy after stem cell transplantation.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine I, University Clinics of the Saarland, Homburg, Germany.

ABSTRACT
Cytomegalovirus (CMV) infection is the most frequent viral complication in patients after allogeneic stem cell transplantation. As CMV replication is tightly controlled by the cellular arm of specific immunity, the kinetics of CMV-specific T cells in association with individual reactivation episodes were prospectively analyzed in 40 allogeneic transplant recipients in a routine clinical setting and evaluated as determinant of impaired CMV control. Antigen-specific CD4 and CD8 T cells were quantified directly from whole blood using intracellular cytokine staining after specific stimulation and MHC class I multimers, respectively. Highly dynamic intraindividual changes of CMV-specific CD4 T cells were observed in patients experiencing CMV viremia. Episodes of CMV reactivation were associated with a drop of CMV-specific CD4 T cells that re-increased after viral clearance (p<0.0001). Furthermore, levels of CMV-specific CD4 T cells at the onset of viremia inversely correlated with peak viral load thereafter (p = 0.02). In contrast, CMV-peptide specific CD8 T cells did not show any association with viremia (p = 0.82). Interestingly, therapeutic dosages of cyclosporine A and corticosteroids led to a dose-dependent reduction of CMV-specific T-cell functions, indicating a causal link between intensified immunosuppressive treatment and CMV reactivation. In conclusion, levels of CMV-specific CD4 T cells inversely correlate with reactivation episodes and may represent a valuable measure to individually guide antiviral therapy after stem cell transplantation.

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Levels of CMV peptide specific CD8 T cells do not correlate with viremia.CMV specific CD8 T cells were quantified using peptide bound MHC class I pentamers. A Dotplots of an HLA-A2 and HLA-B7 positive patient with T cells reactive towards a total of four peptides are shown. B No association of CMV specific CD8 T cells or total CD8 T cells with the presence or absence of detectable viremia (p = 0.82 and p = 0.22, respectively). Bars indicate median T-cell numbers/µl. C CMV specific CD8 T-cell numbers towards individual peptides may show different kinetics over time within one individual. D Higher percentage of PD-1 expressing CD8 T cells in CMV specific CD8 T cells (recognizing HLA-A2 with peptide NLV and/or VLE) as compared to total CD8 T cells (p<0.0001). E No significant difference in the percentage of PD-1 expressing CD8 T cells in CMV specific CD8 T cells (recognizing HLA-A2 with peptide NLV) as compared to total CD8 T cells (p<0.19).
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pone-0003634-g004: Levels of CMV peptide specific CD8 T cells do not correlate with viremia.CMV specific CD8 T cells were quantified using peptide bound MHC class I pentamers. A Dotplots of an HLA-A2 and HLA-B7 positive patient with T cells reactive towards a total of four peptides are shown. B No association of CMV specific CD8 T cells or total CD8 T cells with the presence or absence of detectable viremia (p = 0.82 and p = 0.22, respectively). Bars indicate median T-cell numbers/µl. C CMV specific CD8 T-cell numbers towards individual peptides may show different kinetics over time within one individual. D Higher percentage of PD-1 expressing CD8 T cells in CMV specific CD8 T cells (recognizing HLA-A2 with peptide NLV and/or VLE) as compared to total CD8 T cells (p<0.0001). E No significant difference in the percentage of PD-1 expressing CD8 T cells in CMV specific CD8 T cells (recognizing HLA-A2 with peptide NLV) as compared to total CD8 T cells (p<0.19).

Mentions: Having shown a significant association of a drop in CMV specific CD4 T cells with an increase in viremia as compared to a considerable stability of CMV specific CD8 T-cell levels, the respective relationship of CMV specific CD8 T cells with viral replication was analyzed in a subpopulation of 15 transplant recipients with a panel of five CMV peptide-bound MHC class I pentamers. Based on the requirement for matching of the individual HLA status, between one and four different pentamer-peptide complexes could be analyzed per patient. Typical dotplots of pentamer stainings of CD8 T cells of an HLA-A2 and HLA-B7 positive patient are depicted in figure 4A (see also patient in figure 1C, middle panel). Although fewer episodes of CMV viremia (n = 9) have been studied using MHC class I pentamers, neither CMV specific nor total CD8 T-cell numbers showed any significant decrease upon viremia (figure 4B, p = 0.82 and 0.22, respectively). Moreover, as shown for two patients recognizing two and three peptides, respectively, CMV specific CD8 T-cell responses to single pentamer-peptide complexes within one patient may show profound differences in kinetics over time (figure 4C). Thus examples exist, where the CD8 T-cell responses towards single peptides are continuously rising prior to onset of viremia and thereafter (see left panel, HLA-A*0201-NLV), whereas the response towards other peptides decreases before viremia and increases thereafter (peptides HLA-A*0201-VLE or HLA-A*0101-YSE). Together this indicates that monitoring of CMV specific CD8 T cells using MHC class I multimer staining may be of limited use to identify patients at risk for viral reactivation. Interestingly, however, although numerically stable, CMV specific CD8 T cells in SCT patients exhibit some signs of functional impairment, as the expression of the programmed death 1 (PD-1) receptor on CMV specific CD8 T cells was significantly higher as compared to the whole CD8 T-cell population (Figure 4D, mean values of PD-1 expression on CD8 T cells recognizing the two HLA-A2 binding peptides versus PD-1 expression on whole CD8 T cells, p<0.0001). In contrast, there was no significant difference between the percentage of PD-1 expressing CMV specific CD8 T cells and PD-1 positive pan T cells in healthy individuals (Figure 4E, p = 0.19).


Levels of CMV specific CD4 T cells are dynamic and correlate with CMV viremia after allogeneic stem cell transplantation.

Widmann T, Sester U, Gärtner BC, Schubert J, Pfreundschuh M, Köhler H, Sester M - PLoS ONE (2008)

Levels of CMV peptide specific CD8 T cells do not correlate with viremia.CMV specific CD8 T cells were quantified using peptide bound MHC class I pentamers. A Dotplots of an HLA-A2 and HLA-B7 positive patient with T cells reactive towards a total of four peptides are shown. B No association of CMV specific CD8 T cells or total CD8 T cells with the presence or absence of detectable viremia (p = 0.82 and p = 0.22, respectively). Bars indicate median T-cell numbers/µl. C CMV specific CD8 T-cell numbers towards individual peptides may show different kinetics over time within one individual. D Higher percentage of PD-1 expressing CD8 T cells in CMV specific CD8 T cells (recognizing HLA-A2 with peptide NLV and/or VLE) as compared to total CD8 T cells (p<0.0001). E No significant difference in the percentage of PD-1 expressing CD8 T cells in CMV specific CD8 T cells (recognizing HLA-A2 with peptide NLV) as compared to total CD8 T cells (p<0.19).
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getmorefigures.php?uid=PMC2572846&req=5

pone-0003634-g004: Levels of CMV peptide specific CD8 T cells do not correlate with viremia.CMV specific CD8 T cells were quantified using peptide bound MHC class I pentamers. A Dotplots of an HLA-A2 and HLA-B7 positive patient with T cells reactive towards a total of four peptides are shown. B No association of CMV specific CD8 T cells or total CD8 T cells with the presence or absence of detectable viremia (p = 0.82 and p = 0.22, respectively). Bars indicate median T-cell numbers/µl. C CMV specific CD8 T-cell numbers towards individual peptides may show different kinetics over time within one individual. D Higher percentage of PD-1 expressing CD8 T cells in CMV specific CD8 T cells (recognizing HLA-A2 with peptide NLV and/or VLE) as compared to total CD8 T cells (p<0.0001). E No significant difference in the percentage of PD-1 expressing CD8 T cells in CMV specific CD8 T cells (recognizing HLA-A2 with peptide NLV) as compared to total CD8 T cells (p<0.19).
Mentions: Having shown a significant association of a drop in CMV specific CD4 T cells with an increase in viremia as compared to a considerable stability of CMV specific CD8 T-cell levels, the respective relationship of CMV specific CD8 T cells with viral replication was analyzed in a subpopulation of 15 transplant recipients with a panel of five CMV peptide-bound MHC class I pentamers. Based on the requirement for matching of the individual HLA status, between one and four different pentamer-peptide complexes could be analyzed per patient. Typical dotplots of pentamer stainings of CD8 T cells of an HLA-A2 and HLA-B7 positive patient are depicted in figure 4A (see also patient in figure 1C, middle panel). Although fewer episodes of CMV viremia (n = 9) have been studied using MHC class I pentamers, neither CMV specific nor total CD8 T-cell numbers showed any significant decrease upon viremia (figure 4B, p = 0.82 and 0.22, respectively). Moreover, as shown for two patients recognizing two and three peptides, respectively, CMV specific CD8 T-cell responses to single pentamer-peptide complexes within one patient may show profound differences in kinetics over time (figure 4C). Thus examples exist, where the CD8 T-cell responses towards single peptides are continuously rising prior to onset of viremia and thereafter (see left panel, HLA-A*0201-NLV), whereas the response towards other peptides decreases before viremia and increases thereafter (peptides HLA-A*0201-VLE or HLA-A*0101-YSE). Together this indicates that monitoring of CMV specific CD8 T cells using MHC class I multimer staining may be of limited use to identify patients at risk for viral reactivation. Interestingly, however, although numerically stable, CMV specific CD8 T cells in SCT patients exhibit some signs of functional impairment, as the expression of the programmed death 1 (PD-1) receptor on CMV specific CD8 T cells was significantly higher as compared to the whole CD8 T-cell population (Figure 4D, mean values of PD-1 expression on CD8 T cells recognizing the two HLA-A2 binding peptides versus PD-1 expression on whole CD8 T cells, p<0.0001). In contrast, there was no significant difference between the percentage of PD-1 expressing CMV specific CD8 T cells and PD-1 positive pan T cells in healthy individuals (Figure 4E, p = 0.19).

Bottom Line: In contrast, CMV-peptide specific CD8 T cells did not show any association with viremia (p = 0.82).Interestingly, therapeutic dosages of cyclosporine A and corticosteroids led to a dose-dependent reduction of CMV-specific T-cell functions, indicating a causal link between intensified immunosuppressive treatment and CMV reactivation.In conclusion, levels of CMV-specific CD4 T cells inversely correlate with reactivation episodes and may represent a valuable measure to individually guide antiviral therapy after stem cell transplantation.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine I, University Clinics of the Saarland, Homburg, Germany.

ABSTRACT
Cytomegalovirus (CMV) infection is the most frequent viral complication in patients after allogeneic stem cell transplantation. As CMV replication is tightly controlled by the cellular arm of specific immunity, the kinetics of CMV-specific T cells in association with individual reactivation episodes were prospectively analyzed in 40 allogeneic transplant recipients in a routine clinical setting and evaluated as determinant of impaired CMV control. Antigen-specific CD4 and CD8 T cells were quantified directly from whole blood using intracellular cytokine staining after specific stimulation and MHC class I multimers, respectively. Highly dynamic intraindividual changes of CMV-specific CD4 T cells were observed in patients experiencing CMV viremia. Episodes of CMV reactivation were associated with a drop of CMV-specific CD4 T cells that re-increased after viral clearance (p<0.0001). Furthermore, levels of CMV-specific CD4 T cells at the onset of viremia inversely correlated with peak viral load thereafter (p = 0.02). In contrast, CMV-peptide specific CD8 T cells did not show any association with viremia (p = 0.82). Interestingly, therapeutic dosages of cyclosporine A and corticosteroids led to a dose-dependent reduction of CMV-specific T-cell functions, indicating a causal link between intensified immunosuppressive treatment and CMV reactivation. In conclusion, levels of CMV-specific CD4 T cells inversely correlate with reactivation episodes and may represent a valuable measure to individually guide antiviral therapy after stem cell transplantation.

Show MeSH
Related in: MedlinePlus