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

Mu Nie; Yang Liu; Xiu-xiu Li; Ya-nan Min; Dan-dan Yang; Qiang Li; Qi Feng; Yu Hou; Guo-sheng Li; Jian-zhi Sun; Ming Hou; Yan Shi

doi:10.1055/s-0039-1679909

Thrombosis and Haemostasis, Table of Contents

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^*

¹Department of Hematology, Qilu Hospital, Shandong University, Jinan, China

,

Yang Liu^*

¹Department of Hematology, Qilu Hospital, Shandong University, Jinan, China

,

Xiu-xiu Li

¹Department of Hematology, Qilu Hospital, Shandong University, Jinan, China

,

Ya-nan Min

²Department of Medicine, Karolinska Institutet, Stockholm, Sweden

³Department of Hematology, Affiliated Hospital of Jining Medical University, Jining, Shandong, China

,

Dan-dan Yang

¹Department of Hematology, Qilu Hospital, Shandong University, Jinan, China

,

Qiang Li

¹Department of Hematology, Qilu Hospital, Shandong University, Jinan, China

,

Qi Feng

¹Department of Hematology, Qilu Hospital, Shandong University, Jinan, China

,

Yu Hou

¹Department of Hematology, Qilu Hospital, Shandong University, Jinan, China

,

Guo-sheng Li

¹Department of Hematology, Qilu Hospital, Shandong University, Jinan, China

,

Jian-zhi Sun

¹Department of Hematology, Qilu Hospital, Shandong University, Jinan, China

,

Ming Hou

¹Department of Hematology, Qilu Hospital, Shandong University, Jinan, China

⁴Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan, China

⁵Leading Research Group of Scientific Innovation, Department of Science and Technology of Shandong Province, Qilu Hospital, Shandong University, Jinan, China

,

Yan Shi

¹Department of Hematology, Qilu Hospital, Shandong University, Jinan, China

› Author Affiliations

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

Full Text

References

References
1 McMillan R. The pathogenesis of chronic immune thrombocytopenic purpura. Semin Hematol 2007; 44 (04) (Suppl. 05) S3-S11
2 Gernsheimer T. Chronic idiopathic thrombocytopenic purpura: mechanisms of pathogenesis. Oncologist 2009; 14 (01) 12-21
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
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
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
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
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
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
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
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
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
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
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
14 Dong C, Nurieva RI, Prasad DV. Immune regulation by novel costimulatory molecules. Immunol Res 2003; 28 (01) 39-48
15 Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 2005; 23: 515-548
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
36 McKenzie CG, Guo L, Freedman J, Semple JW. Cellular immune dysfunction in immune thrombocytopenia (ITP). Br J Haematol 2013; 163 (01) 10-23
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
38 Jin HT, Ahmed R, Okazaki T. Role of PD-1 in regulating T-cell immunity. Curr Top Microbiol Immunol 2011; 350: 17-37
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
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
41 Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev 2010; 236: 219-242
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
43 Zhou H, Xiong L, Wang Y. , et al. Treatment of murine lupus with PD-LIg. Clin Immunol 2016; 162: 1-8
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

Supplementary Material

Supplementary Material