Graft-Derived Reconstitution of Mucosal-Associated Invariant T Cells after Allogeneic Hematopoietic Cell Transplantation Abir Bhattacharyya, Laïla-Aïcha.

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Graft-Derived Reconstitution of Mucosal-Associated Invariant T Cells after Allogeneic Hematopoietic Cell Transplantation Abir Bhattacharyya, Laïla-Aïcha Hanafi, Alyssa Sheih, Jonathan L. Golob, Sujatha Srinivasan, Michael J. Boeckh, Steven A. Pergam, Sajid Mahmood, Kelsey K. Baker, Ted A. Gooley, Filippo Milano, David N. Fredricks, Stanley R. Riddell, Cameron J. Turtle Biology of Blood and Marrow Transplantation Volume 24, Issue 2, Pages 242-251 (February 2018) DOI: 10.1016/j.bbmt.2017.10.003 Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 MAIT cell kinetics in blood after HLA-matched or single antigen HLA–mismatched PBSC transplant. (A) Absolute MAIT cell counts in blood from healthy donors (n = 33) and HCT recipients before starting conditioning (pre-HCT, n = 87). (B and C) Absolute MAIT, neutrophil, and lymphocyte counts in blood from MA (B; n = 41) and NMA (C; n = 66) PBSCT recipients. Standard error of mean is shown. (D) MAIT cell counts in blood from healthy donors (n = 33) and PBSCT recipients at 1 year after HCT (n = 47). (E) Absolute MAIT cell counts in blood from MA and NMA recipients after PBSCT. Standard error of mean is shown. (F) Absolute MAIT counts in blood after HCT. Horizontal bars represent the mean. ***P < .001 using the Mann-Whitney test. Biology of Blood and Marrow Transplantation 2018 24, 242-251DOI: (10.1016/j.bbmt.2017.10.003) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 MAIT cells are donor derived and their recovery correlates with graft MAIT content. (A) Percentage of CD69+ MAIT cells from healthy donors (n = 5), PBSC grafts (n = 6), and HCT recipients at the indicated days after transplant (n = 15). Mean ± standard error of the mean is shown. (B) Percentage of Ki67+ MAIT cells from PBSC grafts and HCT recipients on day 10 after HCT. Horizontal bars represent the mean. (C) Percentage of Ki67+ MAIT cells in blood from MA (n = 15) and NMA (n = 11) HCT recipients. Mean ± standard error of the mean is shown. (D) Percent donor chimerism for isolated CD3, CD33, CD56, and MAIT cells after HCT (n = 8). (E and F) The absolute numbers of MAIT cells (E) and CD34+ cells (F) in PBSC grafts and in PBSCT recipients on day 30 (left, n = 17) or day 100 (right, n = 14) after HCT. Log-log linear regression Pearson correlation coefficient r and P values are shown. (G) Shared TCRβ nucleotide sequences in MAIT cells from 42 pairs of healthy donors (HD, n = 7 donors total) and the percentage of TCRβ sequences in MAIT cells from HCT recipients on days 30 and 100 and 1 year after HCT that were also identified in the donor PBSC grafts (top, n = 5). Mean + standard error of the mean is shown. (H) Representative example of TCRβ nucleotide sequences in MAIT cells from a PBSC graft and the recipient on day 30 (middle) and day 100 (right) after HCT. Each point represents a unique nucleotide sequence and its abundance in each sample is shown on the axes. Points on the axes represent nucleotide sequences not shared between samples. *P < .05, **P < .01, ***P < .001 using the Mann-Whitney test. Biology of Blood and Marrow Transplantation 2018 24, 242-251DOI: (10.1016/j.bbmt.2017.10.003) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 MAIT cell reconstitution is impaired in UCB and haploidentical transplants receiving post-HCT cyclophosphamide. (A) Absolute MAIT cell counts in recipients of HLA matched PBSC (n = 107), DUCB (n = 6), and haploidentical PBSC (haplo, n = 6) grafts. Mean ± standard error of the mean is shown. (B) MAIT counts in blood from healthy donors and at 1 year after PBSC and DUCB transplant. Horizontal bars represent the mean. ***P < .001 using the Mann-Whitney test. Biology of Blood and Marrow Transplantation 2018 24, 242-251DOI: (10.1016/j.bbmt.2017.10.003) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Inflammatory cytokines and TCR stimulation are required for full activation and proliferation of MAIT cells. (A) Fold change in mean fluorescence intensity (MFI) of phosphorylated Lck (pY505) (left), ZAP-70 (pY292) (middle), and CD3ζ (pY142) (right) expression in MAIT, naive, central, and effector memory CD8+ T cells from healthy donors (n = 10) after stimulation with the indicated concentrations of OKT3 mAb. Data represent the fold change in MFI of stimulated compared with unstimulated cells. *P < .05, **P < .01, ***P < .001 using paired Student's t-tests comparing phosphoprotein levels in MAIT versus conventional T cell subsets after Bonferroni correction for multiple comparisons. (B) Percentage of MAIT cells from healthy donors (n = 6) expressing CD69 after overnight incubation with inflammatory cytokines (IL-1β, IL-12, IL-18, and IL-23) and/or OKT3 stimulation. P < .01 using t-test comparing OKT3 with cytokines versus cytokines alone. (C) Proliferation of MAIT cells and conventional T cells isolated from healthy donors (n = 9) evaluated by tritiated thymidine incorporation after 4 days incubation with inflammatory cytokines. The stimulation index shows tritiated thymidine incorporation relative to unstimulated cells. Data are mean ± standard error of the mean. Biology of Blood and Marrow Transplantation 2018 24, 242-251DOI: (10.1016/j.bbmt.2017.10.003) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 MAIT cell reconstitution after HCT correlates with the abundance of distinct GI microbial species. (A) TRBV nucleotide sequence diversity as measured by the productive entropy in MAIT cells from healthy donors (n = 3), PBSC grafts (n = 5), and paired HCT recipients (n = 5) at the indicated days after HCT. Lines connect samples from each donor–recipient pair. (B) Percentage of TRBV nucleotide sequences from MAIT cells at day 90 and 1 year after HCT that were also identified at day 30 (left, middle) and of sequences identified at 1 year that were also present at day 90 (right, n = 5). (C) Percentage of total unique TRBV sequences shared between the PBSC graft and the recipient on day 30 or 90 after HCT. Data from 2 representative HCT recipients are shown. Each color represents a unique TRBV nucleotide sequence. (D) Principal components analysis (coordinates 1 and 2) of the composition of the GI microbiota. Each colored line connects samples from a single PBSC recipient at distinct times after HCT (n = 15). Open circles indicate samples collected before HCT, and closed circles are samples collected after HCT. A short distance between points indicates similarity between the composition of the microbiota at each time point. (E) Correlation between blood MAIT cell counts and the relative abundance in stool of Blautia spp. and Bifidobacterium longum (54 paired blood and stool samples). Log-log linear regression Pearson correlation coefficient r and P values are shown. Biology of Blood and Marrow Transplantation 2018 24, 242-251DOI: (10.1016/j.bbmt.2017.10.003) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 6 MAIT counts are lower in HCT recipients who develop grades III to IV acute GVHD and activated MAIT cells suppress CD4+ T cells in vitro. (A) Absolute MAIT cell counts in blood of HCT recipients who did not develop acute GVHD (n = 35) or who developed grades I to II (n = 61) or grades III to IV (n = 8) acute GVHD. Mean ± standard error of the mean is shown. (B) MAIT cells and CD4+ CD25− responder T cells were isolated from the peripheral blood of 3 healthy donors. CFSE-labeled CD4+ responder T cells were stimulated with aCD3/28 beads for 4 days in the presence of MAIT cells or CD4+ responder T cells at a ratio of 1:1, 1:2, 1:4, 1:8, and 1:16 MAIT-to-responder. Representative flow cytometric analysis of CFSE dilution in CD4+ responder T cells. Biology of Blood and Marrow Transplantation 2018 24, 242-251DOI: (10.1016/j.bbmt.2017.10.003) Copyright © 2017 The American Society for Blood and Marrow Transplantation Terms and Conditions