Download PDF
Thromb Haemost 2019; 119(05): 758-765
DOI: 10.1055/s-0039-1679909
Cellular Haemostasis and Platelets
Georg Thieme Verlag KG Stuttgart · New York

PD-1/PD-L Pathway Potentially Involved in ITP Immunopathogenesis

Mu Nie   *
1   Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
,
Yang Liu   *
1   Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
,
Xiu-xiu Li
1   Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
,
Ya-nan Min
2   Department of Medicine, Karolinska Institutet, Stockholm, Sweden
3   Department of Hematology, Affiliated Hospital of Jining Medical University, Jining, Shandong, China
,
Dan-dan Yang
1   Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
,
Qiang Li
1   Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
,
Qi Feng
1   Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
,
Yu Hou
1   Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
,
Guo-sheng Li
1   Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
,
Jian-zhi Sun
1   Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
,
Ming Hou
1   Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
4   Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan, China
5   Leading Research Group of Scientific Innovation, Department of Science and Technology of Shandong Province, Qilu Hospital, Shandong University, Jinan, China
,
Yan Shi
1   Department of Hematology, Qilu Hospital, Shandong University, Jinan, China
› Author Affiliations Funding This work was supported by grants from the National Natural Science Foundation of China (81170475, 81470285, 81770114, 81770133, 81470284), Major Research Plan of National Natural Science Foundation of China (91442204), Natural Science Foundation of Shandong Province (ZR2017PH022, ZR2017PH041) and Major Research Plan of Natural Science Foundation of Shandong Province (ZR2016QZ008).
Further Information

Publication History

13 September 2018

10 January 2019

Publication Date:
26 February 2019 (online)

    Permissions and Reprints

Abstract

The binding of programmed death 1 (PD-1) to its ligands PD-L1 and PD-L2 on antigen-presenting cells turns off autoreactive T cells and induces peripheral tolerance. Aberrant PD-1/PD-L signalling could result in a breakdown of peripheral tolerance and lead to autoimmune diseases. In this study, we detected PD-1 and PD-L expression on T cells and dendritic cells (DCs) in immune thrombocytopenia (ITP) patients with active disease by flow cytometry. The effects of PD-L1-Fc fusion protein (PD-L1-Fc) on T cells and on secretion of interferon-γ (IFN-γ) and interleukin-2 (IL-2) were detected by flow cytometry and enzyme-linked immunosorbent assay, respectively. Compared with healthy controls, PD-1 expression was significantly increased in CD4+ T cells and CD8+ T cells from patients with active ITP. However, PD-L1 expression on monocyte-derived DCs was lower in patients with active ITP than in healthy controls. In vitro assays revealed that PD-L1-Fc increased T cell apoptosis, inhibited activation and proliferation of CD4+ T cells and CD8+ T cells and decreased IFN-γ and IL-2 secretion in patients with active ITP. These results suggest that the aberrant PD-1/PD-L negative co-stimulatory pathway may play a role in ITP. Enhancing PD-1/PD-L signalling might be a promising therapeutic approach for ITP patients by enhancing T cell apoptosis, inhibiting T cell activation and proliferation and reducing secretion of inflammatory factors.

Keywords

immune thrombocytopenia - PD-1 - PD-L1 - PD-L2 - T cell

Authors' Contributions

M.N. and X.-x.L. performed research, analysed data and wrote the manuscript; Y.L., D.-d.Y., Q.L. and Y.H. performed research; Y.-n.M. and Q.F. performed research and analysed data; G.-s.L. and J.-z.S. analysed data; Y.S. contributed vital new reagents, designed the study and wrote the manuscript; M.H. revised the manuscript; and all authors read and edited the manuscript.


Note

Part of this study was orally presented at the 9th Congress of the Asian-Pacific Society on Thrombosis and Hemostasis, Taipei, Taiwan, China, October 6–9, 2016, and part of this study was presented as a poster at the 60th American Society of Hematology Annual Meeting, San Diego, California, United States, December 1–4, 2018.


* M.N. and Y.L. contributed equally to this study.


Supplementary Material

 

  • References

  • 1 McMillan R. The pathogenesis of chronic immune thrombocytopenic purpura. Semin Hematol 2007; 44 (04) (Suppl. 05) S3-S11
    CrossrefPubMedGoogle Scholar
  • 2 Gernsheimer T. Chronic idiopathic thrombocytopenic purpura: mechanisms of pathogenesis. Oncologist 2009; 14 (01) 12-21
    CrossrefPubMedGoogle Scholar
  • 3 Hou M, Stockelberg D, Kutti J, Wadenvik H. Antibodies against platelet GPIb/IX, GPIIb/IIIa, and other platelet antigens in chronic idiopathic thrombocytopenic purpura. Eur J Haematol 1995; 55 (05) 307-314
    PubMedGoogle Scholar
  • 4 Semple JW, Milev Y, Cosgrave D. , et al. Differences in serum cytokine levels in acute and chronic autoimmune thrombocytopenic purpura: relationship to platelet phenotype and antiplatelet T-cell reactivity. Blood 1996; 87 (10) 4245-4254
    CrossrefPubMedGoogle Scholar
  • 5 Olsson B, Andersson PO, Jernås M. , et al. T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura. Nat Med 2003; 9 (09) 1123-1124
    CrossrefPubMedGoogle Scholar
  • 6 Zhang F, Chu X, Wang L. , et al. Cell-mediated lysis of autologous platelets in chronic idiopathic thrombocytopenic purpura. Eur J Haematol 2006; 76 (05) 427-431
    CrossrefPubMedGoogle Scholar
  • 7 Zhao C, Li X, Zhang F, Wang L, Peng J, Hou M. Increased cytotoxic T-lymphocyte-mediated cytotoxicity predominant in patients with idiopathic thrombocytopenic purpura without platelet autoantibodies. Haematologica 2008; 93 (09) 1428-1430
    CrossrefPubMedGoogle Scholar
  • 8 Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 1992; 11 (11) 3887-3895
    CrossrefPubMedGoogle Scholar
  • 9 Vibhakar R, Juan G, Traganos F, Darzynkiewicz Z, Finger LR. Activation-induced expression of human programmed death-1 gene in T-lymphocytes. Exp Cell Res 1997; 232 (01) 25-28
    CrossrefPubMedGoogle Scholar
  • 10 Freeman GJ, Long AJ, Iwai Y. , et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000; 192 (07) 1027-1034
    CrossrefPubMedGoogle Scholar
  • 11 Latchman Y, Wood CR, Chernova T. , et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2001; 2 (03) 261-268
    CrossrefPubMedGoogle Scholar
  • 12 Ishida M, Iwai Y, Tanaka Y. , et al. Differential expression of PD-L1 and PD-L2, ligands for an inhibitory receptor PD-1, in the cells of lymphohematopoietic tissues. Immunol Lett 2002; 84 (01) 57-62
    CrossrefPubMedGoogle Scholar
  • 13 Yamazaki T, Akiba H, Iwai H. , et al. Expression of programmed death 1 ligands by murine T cells and APC. J Immunol 2002; 169 (10) 5538-5545
    CrossrefPubMedGoogle Scholar
  • 14 Dong C, Nurieva RI, Prasad DV. Immune regulation by novel costimulatory molecules. Immunol Res 2003; 28 (01) 39-48
    CrossrefPubMedGoogle Scholar
  • 15 Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 2005; 23: 515-548
    CrossrefPubMedGoogle Scholar
  • 16 Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A 2001; 98 (24) 13866-13871
    CrossrefPubMedGoogle Scholar
  • 17 Tseng SY, Otsuji M, Gorski K. , et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med 2001; 193 (07) 839-846
    CrossrefPubMedGoogle Scholar
  • 18 Nishimura H, Honjo T, Minato N. Facilitation of beta selection and modification of positive selection in the thymus of PD-1-deficient mice. J Exp Med 2000; 191 (05) 891-898
    CrossrefPubMedGoogle Scholar
  • 19 Ansari MJ, Salama AD, Chitnis T. , et al. The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med 2003; 198 (01) 63-69
    CrossrefPubMedGoogle Scholar
  • 20 Fife BT, Guleria I, Gubbels Bupp M. , et al. Insulin-induced remission in new-onset NOD mice is maintained by the PD-1-PD-L1 pathway. J Exp Med 2006; 203 (12) 2737-2747
    CrossrefPubMedGoogle Scholar
  • 21 Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 1999; 11 (02) 141-151
    CrossrefPubMedGoogle Scholar
  • 22 Dolff S, Quandt D, Feldkamp T. , et al. Increased percentages of PD-1 on CD4+ T cells is associated with higher INF-γ production and altered IL-17 production in patients with systemic lupus erythematosus. Scand J Rheumatol 2014; 43 (04) 307-313
    CrossrefPubMedGoogle Scholar
  • 23 Lucas JA, Menke J, Rabacal WA, Schoen FJ, Sharpe AH, Kelley VR. Programmed death ligand 1 regulates a critical checkpoint for autoimmune myocarditis and pneumonitis in MRL mice. J Immunol 2008; 181 (04) 2513-2521
    CrossrefPubMedGoogle Scholar
  • 24 Salama AD, Chitnis T, Imitola J. , et al. Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis. J Exp Med 2003; 198 (01) 71-78
    CrossrefPubMedGoogle Scholar
  • 25 Wang C, Li Y, Proctor TM, Vandenbark AA, Offner H. Down-modulation of programmed death 1 alters regulatory T cells and promotes experimental autoimmune encephalomyelitis. J Neurosci Res 2010; 88 (01) 7-15
    CrossrefPubMedGoogle Scholar
  • 26 Yogev N, Frommer F, Lukas D. , et al. Dendritic cells ameliorate autoimmunity in the CNS by controlling the homeostasis of PD-1 receptor(+) regulatory T cells. Immunity 2012; 37 (02) 264-275
    CrossrefPubMedGoogle Scholar
  • 27 Raptopoulou AP, Bertsias G, Makrygiannakis D. , et al. The programmed death 1/programmed death ligand 1 inhibitory pathway is up-regulated in rheumatoid synovium and regulates peripheral T cell responses in human and murine arthritis. Arthritis Rheum 2010; 62 (07) 1870-1880
    PubMedGoogle Scholar
  • 28 Reynoso ED, Elpek KG, Francisco L. , et al. Intestinal tolerance is converted to autoimmune enteritis upon PD-1 ligand blockade. J Immunol 2009; 182 (04) 2102-2112
    CrossrefPubMedGoogle Scholar
  • 29 Le Roy A, Kempf E, Ackermann F. , et al. Two cases of immune thrombocytopenia associated with pembrolizumab. Eur J Cancer 2016; 54: 172-174
    CrossrefPubMedGoogle Scholar
  • 30 Kanameishi S, Otsuka A, Nonomura Y, Fujisawa A, Endo Y, Kabashima K. Idiopathic thrombocytopenic purpura induced by nivolumab in a metastatic melanoma patient with elevated PD-1 expression on B cells. Ann Oncol 2016; 27 (03) 546-547
    CrossrefPubMedGoogle Scholar
  • 31 Jotatsu T, Oda K, Yamaguchi Y. , et al. Immune-mediated thrombocytopenia and hypothyroidism in a lung cancer patient treated with nivolumab. Immunotherapy 2018; 10 (02) 85-91
    CrossrefPubMedGoogle Scholar
  • 32 Rodeghiero F, Stasi R, Gernsheimer T. , et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 2009; 113 (11) 2386-2393
    CrossrefPubMedGoogle Scholar
  • 33 Min YN, Wang CY, Li XX. , et al. Participation of B-cell-activating factor receptors in the pathogenesis of immune thrombocytopenia. J Thromb Haemost 2016; 14 (03) 559-571
    CrossrefPubMedGoogle Scholar
  • 34 Zhong J, Chen S, Xu L. , et al. Lower expression of PD-1 and PD-L1 in peripheral blood from patients with chronic ITP. Hematology 2016; 21 (09) 552-557
    CrossrefPubMedGoogle Scholar
  • 35 Kinter AL, Godbout EJ, McNally JP. , et al. The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol 2008; 181 (10) 6738-6746
    CrossrefPubMedGoogle Scholar
  • 36 McKenzie CG, Guo L, Freedman J, Semple JW. Cellular immune dysfunction in immune thrombocytopenia (ITP). Br J Haematol 2013; 163 (01) 10-23
    CrossrefPubMedGoogle Scholar
  • 37 Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008; 26: 677-704
    CrossrefPubMedGoogle Scholar
  • 38 Jin HT, Ahmed R, Okazaki T. Role of PD-1 in regulating T-cell immunity. Curr Top Microbiol Immunol 2011; 350: 17-37
    PubMedGoogle Scholar
  • 39 Sheppard KA, Fitz LJ, Lee JM. , et al. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett 2004; 574 (1-3): 37-41
    CrossrefPubMedGoogle Scholar
  • 40 Parry RV, Chemnitz JM, Frauwirth KA. , et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 2005; 25 (21) 9543-9553
    CrossrefPubMedGoogle Scholar
  • 41 Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev 2010; 236: 219-242
    CrossrefPubMedGoogle Scholar
  • 42 Keir ME, Liang SC, Guleria I. , et al. Tissue expression of PD-L1 mediates peripheral T cell tolerance. J Exp Med 2006; 203 (04) 883-895
    CrossrefPubMedGoogle Scholar
  • 43 Zhou H, Xiong L, Wang Y. , et al. Treatment of murine lupus with PD-LIg. Clin Immunol 2016; 162: 1-8
    CrossrefPubMedGoogle Scholar
  • 44 Wang G, Hu P, Yang J, Shen G, Wu X. The effects of PDL-Ig on collagen-induced arthritis. Rheumatol Int 2011; 31 (04) 513-519
    CrossrefPubMedGoogle Scholar