Poorly cytotoxic terminally differentiated CD56negCD16pos NK cells accumulate in Kenyan children with Burkitt lymphomas by Catherine S. Forconi, Cormac.

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Poorly cytotoxic terminally differentiated CD56negCD16pos NK cells accumulate in Kenyan children with Burkitt lymphomas by Catherine S. Forconi, Cormac P. Cosgrove, Pryia Saikumar-Lakshmi, Christina E. Nixon, Joslyn Foley, John Michael Ong’echa, Juliana A. Otieno, Galit Alter, Christian Münz, and Ann M. Moormann BloodAdv Volume 2(10):1101-1114 May 22, 2018 © 2018 by The American Society of Hematology

Catherine S. Forconi et al. Blood Adv 2018;2:1101-1114 © 2018 by The American Society of Hematology

Characterization of NK cell subsets in Kenyan children. Characterization of NK cell subsets in Kenyan children. Children were categorized by malaria and EBV exposure, as well as eBL diagnosis: Nandi (EBVlow/malarialow; n = 10), Kisumu (EBVhigh/malariahigh; n = 10), and eBL patients (n = 14) with no/low EBV and high EBV loads. (A) The percentage of NK cells within the circulating lymphocytes was defined as the number of NK cells (CD56pos and/or CD16pos)/total number of live lymphocytes. (B) Five NK cell subsets were defined by CD56 and CD16 expression levels: CD56brightCD16neg, CD56brightCD16pos, CD56dimCD16neg, CD56dimCD16pos, and CD56negCD16pos. (C) Percentages of NK cell subsets for each group of children within our study. (D) Representative proportions of NK cell subsets in different groups of children. Data in panels A and C are mean ± standard deviation (SD). *P < .05, **P < .01, ***P < .001. Catherine S. Forconi et al. Blood Adv 2018;2:1101-1114 © 2018 by The American Society of Hematology

Comparison of KIR and perforin expression by different NK cell subsets for Nandi, Kisumu, and eBL children. Comparison of KIR and perforin expression by different NK cell subsets for Nandi, Kisumu, and eBL children. Comparison of KIR2DL1S1 (A), KIR2DL1S5 (B), KIR2DL2 (C), KIR2DL3 (D), and KIR3DL1 (E) among the different NK cell subsets: CD56brightCD16neg (1), CD56brightCD16pos (2), CD56dimCD16pos (3), and CD56negCD16pos (4). (F) Expression of KIR3DL1 on CD56negCD16pos NK cells among Nandi, Kisumu, and eBL children. For all KIRs, Nandi, n = 7; Kisumu, n = 5; and BL, n = 10. (G) Perforin expression by NK cell subsets: CD56brightCD16neg (1), CD56brightCD16pos (2), CD56dimCD16pos (3), and CD56negCD16pos (4) (Nandi, n = 4; Kisumu, n = 5; eBL, n = 9). (H) Color code used for data. Data are mean ± SD. *P < .05, **P < .01, ***P < .001, ****P < .0001. n.s., not significant. Catherine S. Forconi et al. Blood Adv 2018;2:1101-1114 © 2018 by The American Society of Hematology

Expression of NKp30, NKp46, and CD161 consistent with an adaptive NK cell phenotype. Expression of NKp30, NKp46, and CD161 consistent with an adaptive NK cell phenotype. NK cell subsets, including CD56brightCD16neg (1), CD56brightCD16pos (2), CD56dimCD16pos (3), and CD56negCD16pos (4), were evaluated for each group of children: Nandi (EBVlow/malarialow), Kisumu (EBVhigh/malariahigh), and eBL patients with low EBV and high EBV load. Comparison of NKp30 (A) and NKp46 (B) expression on the different NK cell subsets across all study groups. NKp30 (C) and NKp46 (D) expression on CD56negCD16pos NK cell subsets across study groups. Nandi, n = 10; Kisumu, n = 8; and BL, n = 11 for NCRs. (E) Comparison of CD161 on the different NK cell subsets across all study groups. (F) CD161 expression on the CD56negCD16pos NK cell subset across study groups. Nandi, n = 8; Kisumu, n = 8; and BL, n = 11 for CD161 expression. Data are mean ± SD. *P < .05, **P < .01, ***P < .001. Catherine S. Forconi et al. Blood Adv 2018;2:1101-1114 © 2018 by The American Society of Hematology

Expression of the NKG2D and 2B4 coactivation receptors on NK cell subsets from Nandi, Kisumu, and eBL children. Expression of the NKG2D and 2B4 coactivation receptors on NK cell subsets from Nandi, Kisumu, and eBL children. NK cell subsets, including CD56brightCD16neg (1), CD56brightCD16pos (2), CD56dimCD16pos (3), and CD56negCD16pos (4), were evaluated for each group of children: Nandi (EBVlow/malarialow), Kisumu (EBVhigh/malariahigh), and BL with low EBV and BL with high EBV. NKG2D expression by (A) NK cell subset representation (A) and by linear representation (B) across study groups (Nandi, n = 8; Kisumu, n = 6; and BL, n = 11). 2B4 expression by NK cells subset representation (C) and by linear representation (D) across study groups (Nandi, n = 6; Kisumu, n = 4; and BL, n = 10). Data are mean ± SD. *P < .05, **P < .01, ***P < .001. Catherine S. Forconi et al. Blood Adv 2018;2:1101-1114 © 2018 by The American Society of Hematology

Absence of the CD57/NKG2C NK cell phenotype otherwise found in HCMV-EBV coinfection. Absence of the CD57/NKG2C NK cell phenotype otherwise found in HCMV-EBV coinfection. NK cell subsets, including CD56brightCD16neg (1), CD56brightCD16pos (2), CD56dimCD16pos (3), and CD56negCD16pos (4), were evaluated for each group of children: Nandi (EBVlow/malarialow), Kisumu (EBVhigh/malariahigh), and eBL patients with no/low EBV and high EBV loads. (A) Comparison of CD57 among the different NK cell subsets across study groups. (B) CD57 expression on the CD56negCD16pos NK cell subset across study groups. (C) Comparison of NKG2C expression among different NK cell subsets across groups of children. (D) NKG2C expression on the CD56negCD16pos NK cell subset across study groups. (E) Median fluorescence intensity (MFI) of antibody titers against CMV. (F) Coexpression of CD57 and NKG2C on CD56dimCD16pos and CD56negCD16pos NK cells. (G) CD57posNKG2Cpos expression between CD56dimCD16pos and CD56negCD16pos subsets across study groups. For CD57, Nandi, n = 8; Kisumu, n = 6, and BL, n = 11. For NKG2C, Nandi, n = 7; Kisumu, n = 5; and BL, n = 11. Data are mean ± SD. *P < .05, **P < .01, ***P < .001. Catherine S. Forconi et al. Blood Adv 2018;2:1101-1114 © 2018 by The American Society of Hematology

MIP-1β production and degranulation of CD56neg CD16pos NK cell subset after K562 cell stimulation. MIP-1β production and degranulation of CD56negCD16posNK cell subset after K562 cell stimulation. PBMCs from healthy children (Nandi and Kisumu; n = 7) and eBL children (n = 7) were stimulated with K562 cells in a functional in vitro killing assay. NK cell subsets were defined by CD56 and CD16 expression levels. (A) Percentage of MIP-1βpos NK cells in each subset, with and without stimulation. (B) Percentage of TNF-αpos NK cells in each subset, with and without stimulation. (C) Comparison of MIP-1β, TNF-α, CD107a, and IFN-γ positive cells after K562 cell stimulation between the CD56dimCD16pos and CD56negCD16pos NK cell subsets. The Wilcoxon test was used for related data, and Mann-Whitney U test was used for nonrelated data. Data are mean ± SD. *P < .05. Catherine S. Forconi et al. Blood Adv 2018;2:1101-1114 © 2018 by The American Society of Hematology

Resolution of the CD56neg CD16pos subset from eBL children after chemotherapy. Resolution of the CD56negCD16possubset from eBL children after chemotherapy. NK cell subsets were defined by CD56 and CD16 expression. The first time point was before chemotherapy, and the second and third time points were 3 and 9 months, respectively, after diagnosis (during remission). (A) Changes in the percentage of NK cells were defined as the number of NK cells (CD56pos and/or CD16pos)/total number of live lymphocytes. (B) Changes in the percentage of CD56negCD16pos NK cells at each time point for 2 eBL patients. (C) Cytograms for the 3 time points for patient “BL1.” Changes in activation (D) and NCR (E) markers over time for both eBL children (“BL1” and “BL2”) for CD56negCD16pos NK cells. (F) Plots of NKp30/NKp46, NKp30/2B4, and NKp46/2B4 coexpression for CD56negCD16pos NK cells from an eBL1 patient during the course of treatment, as well as for 3 healthy Nandi children. Catherine S. Forconi et al. Blood Adv 2018;2:1101-1114 © 2018 by The American Society of Hematology