Modification of cellular and humoral immunity by somatically reverted T cells in X-linked lymphoproliferative syndrome type 1 Akihiro Hoshino, MD, PhD,

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Presentation transcript:

Modification of cellular and humoral immunity by somatically reverted T cells in X-linked lymphoproliferative syndrome type 1 Akihiro Hoshino, MD, PhD, Xi Yang, MD, PhD, Kay Tanita, MD, Kenichi Yoshida, MD, PhD, Toshiaki Ono, MD, PhD, Naonori Nishida, MD, PhD, Yusuke Okuno, MD, PhD, Takeyuki Kanzaki, MD, PhD, Kumiko Goi, MD, PhD, Hisanori Fujino, MD, PhD, Koichi Ohshima, MD, PhD, Yuichi Shiraishi, MD, PhD, Kenichi Chiba, BA, Hiroko Tanaka, BS, Satoru Miyano, PhD, Seishi Ogawa, MD, PhD, Seiji Kojima, MD, PhD, Tomohiro Morio, MD, PhD, Hirokazu Kanegane, MD, PhD Journal of Allergy and Clinical Immunology Volume 143, Issue 1, Pages 421-424.e11 (January 2019) DOI: 10.1016/j.jaci.2018.07.044 Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 The survival curves of patients with XLP1 and characteristics of the studied family. A, The overall survival of transplanted versus untransplanted patients (P < .0001, log-rank test). B, The transplantation-free survival of reverted versus nonreverted patients (P = .036, generalized Wilcoxon test). C, Pedigree of the family. D, Sanger sequencing of the SH2D1A gene. The blue arrows indicate mutated sequences. The red arrow indicates the reverted wild-type sequence. E, SAP expression in CD8+ and CD4+ T cells. Each number indicates the percentage of SAP+ cells in CD8+ or CD4+ T cells. Journal of Allergy and Clinical Immunology 2019 143, 421-424.e11DOI: (10.1016/j.jaci.2018.07.044) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Function of somatically reverted T cells. A. MHC class I/EBV peptide tetramer analysis of CD8+ T cells. The numbers indicate the percentage of tetramer-positive cells in SAP− and SAP+ CD8+ T cells. B, CD137 expression analysis of CD8+ T cells after stimulation. Red bars indicate mean ± SD of the controls (n = 3). C, Proliferation analysis of CD8+ and CD4+ T cells after stimulation. The numbers indicate the percentage of divided cells in SAP− and SAP+ cells. D, Cytotoxicity assay against autologous EBV-LCLs. Red, healthy control; blue, reverted patient (P25.3); green, nonreverted patient (P24.1). E, IL-10 expression analysis of CD4+ T cells. The numbers indicate the percentage of IL-10–producing cells in SAP− and SAP+ CD4+ T cells. F, Inducible costimulator expression analysis in unstimulated CD4+ T cells (gray shaded areas) and stimulated CD4+ T cells (red shaded areas). Journal of Allergy and Clinical Immunology 2019 143, 421-424.e11DOI: (10.1016/j.jaci.2018.07.044) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Histopathological study of a cervical lymph node. A, Large and medium-sized lymphoid cell proliferation is observed (hematoxylin-eosin stain, 400×). B, Most of the large lymphoid cells are positive for CD20 (400×). C, The large lymphoid cells are positive for EBER (400×). Journal of Allergy and Clinical Immunology 2019 143, 421-424.e11DOI: (10.1016/j.jaci.2018.07.044) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Genetic analysis of the family members. Sanger sequencing of SH2D1A gene. Journal of Allergy and Clinical Immunology 2019 143, 421-424.e11DOI: (10.1016/j.jaci.2018.07.044) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Distribution of T-cell subsets. A, Flow cytometry gating strategy for identification of naive T cell (Tnaive, CD45RO− CD62L+), central memory T cell (TCM, CD45RO+ CD62L+), effector memory T cell (TEM, CD45RO+ CD62L−), and terminally differentiated effector memory T cell (TEMRA, CD45RO−CD62L−). SAP+ CD8+ T cells from control and P25.3 were shown. B, Distribution of T-cell subsets in SAP+ and SAP− T cells. Control data are the mean obtained from 6 healthy adults. Journal of Allergy and Clinical Immunology 2019 143, 421-424.e11DOI: (10.1016/j.jaci.2018.07.044) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 CD137 expression analysis of CD4+ T cells. CD137 expression analysis of CD4+ T cells after stimulation. Red bars indicate mean ± SD of the controls (n = 3). Journal of Allergy and Clinical Immunology 2019 143, 421-424.e11DOI: (10.1016/j.jaci.2018.07.044) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Characteristics of the expanded cells after stimulation of EBV peptides. A, Distribution of T-cell subsets. B, The frequency of SAP-positive cells in total expanded cells. Journal of Allergy and Clinical Immunology 2019 143, 421-424.e11DOI: (10.1016/j.jaci.2018.07.044) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 IFN-γ production and CD107a expression after EBV-LCL stimulation. A, IFN-γ production in CD4+ and CD8+ T cells. B, CD107a expression on CD8+ T cells. Journal of Allergy and Clinical Immunology 2019 143, 421-424.e11DOI: (10.1016/j.jaci.2018.07.044) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions