Adaptive Natural Killer Cell and Killer Cell Immunoglobulin–Like Receptor–Expressing T Cell Responses are Induced by Cytomegalovirus and Are Associated.

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Adaptive Natural Killer Cell and Killer Cell Immunoglobulin–Like Receptor–Expressing T Cell Responses are Induced by Cytomegalovirus and Are Associated with Protection against Cytomegalovirus Reactivation after Allogeneic Donor Hematopoietic Cell Transplantation Zachary B. Davis, Sarah A. Cooley, Frank Cichocki, Martin Felices, Rose Wangen, Xianghua Luo, Todd E. DeFor, Yenan T. Bryceson, Don J. Diamond, Claudio Brunstein, Bruce R. Blazar, John E. Wagner, Daniel J. Weisdorf, Amir Horowitz, Lisbeth A. Guethlein, Peter Parham, Michael R. Verneris, Jeffrey S. Miller Biology of Blood and Marrow Transplantation Volume 21, Issue 9, Pages 1653-1662 (September 2015) DOI: 10.1016/j.bbmt.2015.05.025 Copyright © 2015 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Recipient CMV Sero+/React− and React+ results in expansion of KIR2DL2/3+ and NKG2C+CD57+ NK cells after transplantation. (A) NKG2C+CD57+ cells were evaluated from Sero−/React− (black bars, n = 91), Sero+/React− (light gray bars, n = 53) and CMV React+ (white bars, n = 59), (B) NKG2C+CD57−, (C) NKG2A+, (D) KIR2DL1+, (E) KIR2DL2/3+, and (F) KIR3DL1+ expression was evaluated on CD56+CD3− NK cells after transplantation from CMV Sero−/React− (black bars, n = 116), Sero+/React− (light gray bars, n = 54), and CMV React+ (white bars, n = 57). Recipient samples were analyzed at 100 days, 6 months, and 1 year after transplantation. Bars represent the mean percentage of lymphocytes expressing each phenotype ± SEM. T test (equal variance or unequal variance t-test, based on variance test result) was used for the pairwise comparisons between groups at each time point. ∗P < .05, ∗∗P < .01, ∗∗∗P < .001. Biology of Blood and Marrow Transplantation 2015 21, 1653-1662DOI: (10.1016/j.bbmt.2015.05.025) Copyright © 2015 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Recipient CMV Sero+/React− and React+ results in expansion of KIR2DL2/3+ and NKG2C+CD57+ CD56+CD3+ T cells after HCT. (A) NKG2C+CD57+ CD56+CD3+ T cells in CMV Sero−/React− (black bars, n = 116), Sero+/React− (light gray bars, n = 53), and CMV React+ (white bars, n = 57), (B) NKG2C+CD57−, (C) NKG2A+, (D) KIR2DL1+, (E) KIR2DL2/3+ and (F) KIR3DL1+ expression was evaluated on CD56+CD3+ T cells from CMV Sero−/React− (black bars, n = 115), Sero+/React− (light gray bars, n = 54), and CMV React+ (white bars, n = 57). Analysis as in Figure 1. ∗P < .05, ∗∗P < .01, ∗∗∗P < .001. Biology of Blood and Marrow Transplantation 2015 21, 1653-1662DOI: (10.1016/j.bbmt.2015.05.025) Copyright © 2015 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 CMV Sero+/React− and React+ results in expansion of KIR2DL2/3+ and NKG2C+CD57+ CD56−CD3+ T cells after HCT. (A) NKG2C+CD57+ T cells in Sero−/React− (black bars, n = 116), Sero+/React− (light gray bars, n = 54), and CMV React+ (white bars, n = 57), (B) NKG2C+CD57−, (C) NKG2A+, (D) KIR2DL1+, (E) KIR2DL2/3+, and (F) KIR3DL1+ CD56-CD3+ T cells were evaluated from Sero−/React− (black bars, n = 116), Sero+/React− (light gray bars, n = 54) and CMV React+ (white bars, n = 57). Analysis as in Figure 1. ∗P < .05, ∗∗P < .01, ∗∗∗P < .001. Biology of Blood and Marrow Transplantation 2015 21, 1653-1662DOI: (10.1016/j.bbmt.2015.05.025) Copyright © 2015 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Recipient CMV Sero+ is associated with increased KIR2DL2/3 and NKG2C expressing adaptive CD56+CD3− NK cells in React− recipients of sibling but not UCB grafts. CD56+CD3− NK cells from CMV Sero−/React− (▴, n = 77) or CMV Sero+/React− (□, n = 50). Shown are the percentage of cells expressing (A) KIR2DL2/3+, (B) NKG2A+, (C) NKG2C+CD57+ or (D) NKG2C+CD57−. The same subsets are shown for React− UCB HCT who were either CMV Sero−/React− (▴, n = 61) or CMV Sero+/React− (□, n = 47) (E-H). Analysis as in Figures 1 through 3. ∗P < .05, ∗∗P < .01, ∗∗∗P < .001. Biology of Blood and Marrow Transplantation 2015 21, 1653-1662DOI: (10.1016/j.bbmt.2015.05.025) Copyright © 2015 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 Recipient CMV sero+ is associated with increased KIR2DL2/3 and NKG2C expressing adaptive CD56+CD3+ T cells in React− recipients of sibling but not UCB grafts. CD56+CD3+ T cells CMV Sero−/React− (▴, n = 73) or CMV Sero+/React− (□, n = 106). Shown are the percentage of cells expressing (A) KIR2DL2/3+, (B) NKG2A+, (C) NKG2C+CD57+, or (D) NKG2C+CD57−. The same subsets are shown for React− UCB HCT who were either CMV Sero−/React− (▴, n = 59) or CMV Sero+/React− (□, n = 47) (E-H). Analysis as in Figures 1 through 3 *P < .05, **P < .01, ***P < .001. Biology of Blood and Marrow Transplantation 2015 21, 1653-1662DOI: (10.1016/j.bbmt.2015.05.025) Copyright © 2015 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 6 Cumulative incidence of CMV reactivation is lower in sibling versus UCB grafts, regardless of donor serostatus. Sibling donor Sero+, n = 63; 37% CMV reactivation; donor Sero−, n = 61; 33% CMV reactivation) versus UCB grafts (n = 270; 51% CMV reactivation). Biology of Blood and Marrow Transplantation 2015 21, 1653-1662DOI: (10.1016/j.bbmt.2015.05.025) Copyright © 2015 American Society for Blood and Marrow Transplantation Terms and Conditions