Early Cytomegalovirus Reactivation Leaves a Specific and Dynamic Imprint on the Reconstituting T Cell Compartment Long-Term after Hematopoietic Stem Cell.

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Early Cytomegalovirus Reactivation Leaves a Specific and Dynamic Imprint on the Reconstituting T Cell Compartment Long-Term after Hematopoietic Stem Cell Transplantation Gertjan Lugthart, Monique M. van Ostaijen-ten Dam, Cornelia M. Jol - van der Zijde, Tessa C. van Holten, Michel G.D. Kester, Mirjam H.M. Heemskerk, Robbert G.M. Bredius, Maarten J.D. van Tol, Arjan C. Lankester Biology of Blood and Marrow Transplantation Volume 20, Issue 5, Pages 655-661 (May 2014) DOI: 10.1016/j.bbmt.2014.01.018 Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Impact of early CMV reactivation on lymphocyte numbers and subsets 1 year after HSCT. (A) Absolute numbers of lymphocytes, CD3+ T cells, CD3−CD19+ B cells, and CD3−CD56+ NK cells and (B) CD8+ T cells, CD4+ T cells, and T cell receptor γδ+ T cells from 85 patients without CMV reactivation (white bars, CMV DNA load always < 1.7 log copies/mL [c/mL]) and 46 patients with CMV reactivation (gray bars, CMV DNA load ≥ 1x >1.7 log). (C) Absolute numbers of CD8+ T cells of 85 patients without detectable CMV reactivation (white bars), 13 patients with detectable CMV DNA in plasma but not ≥ 3 log c/mL at 2 consecutive time points (light gray bars) and 33 patients with a CMV load ≥ 3 log c/mL at 2 or more consecutive time points (dark gray bars). Shown are cells/μL of peripheral blood 1 year after HSCT. Bars: median, interquartile range and overall range. P values: Mann-Whitney test; NS indicates P > .05; ***P < .001; **** P < .0001. Biology of Blood and Marrow Transplantation 2014 20, 655-661DOI: (10.1016/j.bbmt.2014.01.018) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Influence of pretransplantation CMV serostatus and early EBV and HAdV reactivation. (A) Impact of donor and recipient pretransplantation CMV serostatus on CD8+ T cell numbers in patients without CMV reactivation (white bars, +/+: n = 14, +/−: n = 12, −/+: n = 13 and −/−: n = 46) and patients with CMV reactivation (gray bars, +/+: n = 28, +/−: n = 8 and −/+, n = 10). (B & C) Absolute numbers of CD3+, CD4+, CD8+, and T cell receptor γδ+ T cell in 85 patients without CMV reactivation. (B) Shows 35 patients without versus 50 patients with early Epstein-Barr virus (EBV) reactivation and (C) shows 65 patients without versus 20 patients with early human adenovirus (HAdV) reactivation. White bars (−): plasma DNA load always < 1.7 log. Gray bars (+): plasma DNA load at least once > 1.7 log. Shown are cells/μL of peripheral blood 1 year after HSCT. Bars: median, interquartile range and overall range, P values: Kruskall-Wallis test (A) or Mann-Whitney test (B & C). NS indicates P > .05; *P < .05. Biology of Blood and Marrow Transplantation 2014 20, 655-661DOI: (10.1016/j.bbmt.2014.01.018) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Early CMV reactivation and T cell differentiation one year after HSCT. Absolute numbers (left panels) and relative contribution (right panels) of T cell differentiation stages to the (A) CD8+ and (B) CD4+ T cell subsets in a subcohort of 35 patients without (−) and 18 patients with (+) CMV reactivation. N: naive (very light gray, CD45RA+ CCR7+), CM: central memory (light gray, CD45RA− CCR7+), EM: effector memory (gray, CD45RA− CCR7-), EMRA (dark gray, CD45RA+ CCR7−). Absolute numbers: shown are cells/μL of peripheral blood 1 year after HSCT. Bars: median, interquartile range and overall range. P values: Mann-Whitney test; NS indicates P >.05; ****P < .0001. Relative contribution: bars show mean percentage of the CD8+ or CD4+ T cell subset with standard error of the mean. Biology of Blood and Marrow Transplantation 2014 20, 655-661DOI: (10.1016/j.bbmt.2014.01.018) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Dynamics of CD8+ T cell reconstitution in patients with early CMV reactivation. (A) CD8+ T cell reconstitution after CMV clearance in 21 patients with a primary CD8+ T cell recovery < 500 cells/μL and 25 patients with a primary recovery > 500 cells/μL. Shown are cells/μL of peripheral blood at the moment of CMV clearance (C), .5 year and 1 year after HSCT. Bars: median, interquartile range and overall range. Lines connect median values. P values: Wilcoxon matched-pairs signed rank test. NS indicates P >.05; ***P < .001; ****P < .0001. (B) Absolute numbers of T cell differentiation stages 1 year after HSCT in 9 patients with a primary CD8+ T cell recovery < 500 cells/μL and 9 patients with a primary recovery > 500 cells/μL. N: naive (very light gray, CD45RA+ CCR7+), CM: central memory (light gray, CD45RA− CCR7+), EM: effector memory (gray, CD45RA− CCR7−), EMRA (dark gray, CD45RA+ CCR7−). Shown are cells/μL of peripheral blood 1 year after HSCT. Bars: median, interquartile range and overall range. P values: Mann-Whitney test; NS indicates P > .05; *P < .05. Biology of Blood and Marrow Transplantation 2014 20, 655-661DOI: (10.1016/j.bbmt.2014.01.018) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 Dynamics of T cell reconstitution 1 and 2 years after HSCT. (A) Paired analysis of absolute numbers of CD8+ and CD4+ T cells in 42 patients without and 34 patients with early CMV reactivation at 1 and 2 years after HSCT. Shown are cells/μL of peripheral blood 1 and 2 years after HSCT. (B & C) Paired analysis of absolute numbers of (B) CD8+ and (C) CD4+ N, CM, EM, and EMRA T cells in 19 patients without (−) and 12 patients with (+) CMV reactivation at 1 and 2 years after HSCT. N: naive (very light gray, CD45RA+ CCR7+), CM: central memory (light gray, CD45RA− CCR7+), EM: effector memory (gray, CD45RA− CCR7−), EMRA (dark gray, CD45RA+ CCR7−). Shown are cells/μL of peripheral blood 1 and 2 years after HSCT. Bars (A): median, interquartile range and overall range. Diamonds (B & C): Median and interquartile range. Lines connect median values 1 and 2 years after HSCT. Arrows (↑/↓): increase/reduction. P values: Wilcoxon matched-pairs signed rank test. = indicates P > .10; NS, .05 < P < .10; *P < .05; **P < .01; ****P < .0001. Biology of Blood and Marrow Transplantation 2014 20, 655-661DOI: (10.1016/j.bbmt.2014.01.018) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure S1 Biology of Blood and Marrow Transplantation 2014 20, 655-661DOI: (10.1016/j.bbmt.2014.01.018) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure S2 Biology of Blood and Marrow Transplantation 2014 20, 655-661DOI: (10.1016/j.bbmt.2014.01.018) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure S3 Biology of Blood and Marrow Transplantation 2014 20, 655-661DOI: (10.1016/j.bbmt.2014.01.018) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure S4 Biology of Blood and Marrow Transplantation 2014 20, 655-661DOI: (10.1016/j.bbmt.2014.01.018) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions