Expansion of NKG2A−LIR1− Natural Killer Cells in HLA-Matched, Killer Cell Immunoglobulin-Like Receptors/HLA-Ligand Mismatched Patients following Hematopoietic.

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Expansion of NKG2A−LIR1− Natural Killer Cells in HLA-Matched, Killer Cell Immunoglobulin-Like Receptors/HLA-Ligand Mismatched Patients following Hematopoietic Cell Transplantation Silvia Rathmann, Sabine Glatzel, Kathrin Schönberg, Markus Uhrberg, Marie Follo, Christian Schulz-Huotari, Markus Kaymer, Hendrik Veelken, Jürgen Finke, Paul Fisch Biology of Blood and Marrow Transplantation Volume 16, Issue 4, Pages 469-481 (April 2010) DOI: 10.1016/j.bbmt.2009.12.008 Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Characterization of effector cells positive or negative for NKG2A/LIR1 inhibitory receptors in patients before HCT and their donors. The numbers of NK cells, NKT-like cells (TCR αβ+, CD56+) and γδ T cells were gated on (A) all NKG2A– LIR1–, as well as on (B) NKG2A+ and/or LIR1+ effector cells. “NKG2A+ and/or LIR1+ effector cells” include the NKG2A+ LIR1–, the LIR1– NKG2A+, and the LIR1+ NKG2A+ cell populations. Cell numbers were determined by flow cytometry from a total of 20,000 cells in patients before HCT and their donors. Highly statistical significant differences (Mann-Whitney U-Test) (P < .001) are indicated by ∗∗. Biology of Blood and Marrow Transplantation 2010 16, 469-481DOI: (10.1016/j.bbmt.2009.12.008) Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 NKG2A/LIR1 expression on NK cells of representative KIR/HLA-ligand mismatched donor/patient pairs. The NK cells of particular donors and representative patients #28, #30, and #34 were analyzed for NKG2A/LIR1 expression by gating on CD3− CD56+ lymphocytes before HCT (pre Tx) and at different time points following HCT. Biology of Blood and Marrow Transplantation 2010 16, 469-481DOI: (10.1016/j.bbmt.2009.12.008) Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 NK cell levels following HCT analyzed by the donor KIR haplotype. The numbers of (A) NKG2A– LIR1– NK cells and (B) NKG2A+ and/or LIR1+ NK cells, determined from a total of 20,000 effector cells by flow cytometry at different time points following HCT, were analyzed in the donors and their recipients according to the A/B and A/A KIR haplotypes. Patients of the B/B haplotype were not included in this analysis because 5 of 6 B/B patients were KIR-ligand matched. Biology of Blood and Marrow Transplantation 2010 16, 469-481DOI: (10.1016/j.bbmt.2009.12.008) Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Effector cells positive or negative for NKG2A/LIR1 inhibitory receptors in the posttransplant course. The numbers of NKG2A– LIR1– NK cells as well as NKG2A+ and/or LIR1+ NK cells in patients in CR and in relapse were measured by flow cytometry on days 112, 140, and 168 following HCT. “NKG2A+ and/or LIR1 + NK cells” include the NKG2A+ LIR1–, the LIR1– NKG2A+, and the LIR1+ NKG2A+ subpopulations. The number of patients (n) in both groups at each of these time points is shown on the right. Statistically significant differences (Mann-Whitney U-test) (P < .05) are indicated by ∗ and highly significant differences (P < .001) are indicated by ∗∗. Biology of Blood and Marrow Transplantation 2010 16, 469-481DOI: (10.1016/j.bbmt.2009.12.008) Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 Comparison of NKG2A– LIR1– NK cell subpopulations in KIR/HLA-ligand mismatched and KIR/HLA-ligand matched patients. NKG2A– LIR1– NK cells were measured in KIR/HLA-ligand mismatched and KIR/HLA-ligand matched transplanted patients before HCT (pre Tx) and at different time points following HCT until day 168. The numbers of all NKG2A– LIR1– NK cells from a total of 20,000 lymphocytes for each patient are compared. For each time point, the numbers of patients (n) analyzed in the KIR/HLA-ligand mismatched and matched groups are given. Statistically significant differences between the groups are indicated by ∗ (Mann-Whitney U-test). Biology of Blood and Marrow Transplantation 2010 16, 469-481DOI: (10.1016/j.bbmt.2009.12.008) Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 6 Subpopulations of NKG2A– LIR1– NK cells expressing individual KIR and their alloreactive potential. (A) The numbers of NKG2A– LIR1– NK cells, expressing different KIR, from KIR/HLA-ligand mismatched patients #21 and #28 before (pre Tx) and at several time points following HCT, compared to their donors. NK cell subsets expressing the KIR for which the patients had no HLA class I ligand (marked by an arrow). (B) CD107a expression and intracellular IFN-γ secretion following stimulation by medium or K562 cells were measured by flow cytometry in subpopulations of the NKG2A– LIR1– NK cells from patients #21 (days 331 post-HCT) and #28 (day 357) (subsets indicated above the dot plots), expressing KIR for which the patients had no HLA class I ligands (outlined by a frame). The percentages of positive cells are indicated in the quadrants. KIR2DL2/L3/S2+ or KIR3DL1/S1+ gated dot plots included NKG2A– LIR1– NK cells expressing other inhibitory KIR. Analysis of dot plots gated on multiple KIR was restricted to NK cells expressing the mismatched KIR as their only inhibitory receptors (for patient #21 KIR2DL2/L3/S2+ and/or KIR3DL1/S1+ and for #28 KIR3DL1/S1+) (for the KIR genotype see Tables 2/S1). Biology of Blood and Marrow Transplantation 2010 16, 469-481DOI: (10.1016/j.bbmt.2009.12.008) Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 7 Activating receptors on NK cells following KIR/HLA-ligand matched and mismatched HCT. The mean fluorescence index (MFI) was determined by flow cytometry for the activating receptors 2B4, NKG2D, NKp30, NKp44, and NKp46 expressed by NK cells from KIR/HLA-ligand mismatched and KIR/HLA-ligand matched transplanted patients before HCT (pre Tx) and at different time points following HCT. The numbers of patients (n) in the KIR/HLA-ligand mismatched and matched groups for each time point are indicated on the right. Statistically significant differences between the KIR/HLA-ligand mismatched and matched patients are indicated (∗). Biology of Blood and Marrow Transplantation 2010 16, 469-481DOI: (10.1016/j.bbmt.2009.12.008) Copyright © 2010 American Society for Blood and Marrow Transplantation Terms and Conditions