Comprehensive assessment of peripheral blood TCRβ repertoire in infectious mononucleosis and chronic active EBV infection patients
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Epstein-Barr virus (EBV) primary infection is usually asymptomatic, but it sometimes progresses to infectious mononucleosis (IM). Occasionally, some people develop chronic active EBV infection (CAEBV) with underlying immunodeficiency, which belongs to a continuous spectrum of EBV-associated lymphoproliferative disorders (EBV+ LPD) with heterogeneous clinical presentations and high mortality. It has been well established that T cell-mediated immune response plays a critical role in the disease evolution of EBV infection. Recently, high-throughput sequencing of the hypervariable complementarity-determining region 3 (CDR3) segments of the T cell receptor (T cell receptor β (TCRβ)) has emerged as a sensitive approach to assess the T cell repertoire. In this study, we fully characterized the diversity of peripheral blood TCRβ repertoire in IM (n = 6) and CAEBV patients (n = 5) and EBV-seropositive controls (n = 5). Compared with the healthy EBV-seropositive controls, both IM and CAEBV patients demonstrate a significant decrease in peripheral blood TCRβ repertoire diversity, basically, including narrowed repertoire breadth, highly expanded clones, and skewed CDR3 length distribution. However, there is no significant difference between IM and CAEBV patients. Furthermore, we observed some disease-related preferences in TRBV/TRBJ usage and combinations, as well as lots of T cell clones shared by different groups (unique or overlapped) involved in public T cell responses, which provide more detailed insights into the divergent disease evolution.
KeywordsEpstein-Barr virus (EBV) Infectious mononucleosis (IM) Chronic active EBV infection (CAEBV) T cell receptor (TCRβ) repertoire complementarity-determining region 3 (CDR3)
Chronic active EBV infection
T cell receptor β
Hypervariable complementarity-determining region 3
- EBV+ LPD
EBV-associated lymphoproliferative disorders
Cytotoxic T lymphocytes
This study was supported by the National Natural Science Foundation of China (grant no. 81371737) and the Basic Research Program of Shenzhen Innovation Council of China (grant no. JCYJ20130402114702128).
Compliance with ethical standards
All procedures were performed according to the ethical standards of the Declaration of Helsinki involving human subjects in medical research. All participants gave written informed consent.
Conflict of interest
The authors declare that they have no conflict of interest.
- 3.Balfour HH Jr, Sifakis F, Sliman JA, Knight JA, Schmeling DO, Thomas W (2013) Age-specific prevalence of Epstein-Barr virus infection among individuals aged 6-19 years in the United States and factors affecting its acquisition. J Infect Dis 208(8):1286–1293. doi: 10.1093/infdis/jit321 CrossRefPubMedGoogle Scholar
- 5.Ohshima K, Kimura H, Yoshino T, Kim CW, Ko YH, Lee SS, Peh SC, Chan JK, Group CS (2008) Proposed categorization of pathological states of EBV-associated T/natural killer-cell lymphoproliferative disorder (LPD) in children and young adults: overlap with chronic active EBV infection and infantile fulminant EBV T-LPD. Pathol Int 58(4):209–217. doi: 10.1111/j.1440-1827.2008.02213.x CrossRefPubMedGoogle Scholar
- 7.Kimura H, Morishima T, Kanegane H, Ohga S, Hoshino Y, Maeda A, Imai S, Okano M, Morio T, Yokota S, Tsuchiya S, Yachie A, Imashuku S, Kawa K, Wakiguchi H, Japanese Association for Research on Epstein-Barr V, Related D (2003) Prognostic factors for chronic active Epstein-Barr virus infection. J Infect Dis 187(4):527–533. doi: 10.1086/367988 CrossRefPubMedGoogle Scholar
- 10.Kuzushima K, Hayashi N, Kudoh A, Akatsuka Y, Tsujimura K, Morishima Y, Tsurumi T (2003) Tetramer-assisted identification and characterization of epitopes recognized by HLA A*2402-restricted Epstein-Barr virus-specific CD8+ T cells. Blood 101(4):1460–1468. doi: 10.1182/blood-2002-04-1240 CrossRefPubMedGoogle Scholar
- 17.Boyd SD, Marshall EL, Merker JD, Maniar JM, Zhang LN, Sahaf B, Jones CD, Simen BB, Hanczaruk B, Nguyen KD, Nadeau KC, Egholm M, Miklos DB, Zehnder JL, Fire AZ (2009) Measurement and clinical monitoring of human lymphocyte clonality by massively parallel VDJ pyrosequencing. Sci Transl Med 1(12):12ra23CrossRefPubMedPubMedCentralGoogle Scholar
- 19.Lima M, Teixeira MA, Queirós ML, Santos AH, Gonçalves C, Correia J, Farinha F, Mendonça F, Soares JMN, Almeida J, Orfão A, Justiça B (2003) Immunophenotype and TCR-Vβ repertoire of peripheral blood T-cells in acute infectious mononucleosis. Blood Cell Mol Dis 30(1):1–12. doi: 10.1016/s1079-9796(03)00014-7 CrossRefGoogle Scholar
- 23.Robins HS, Campregher PV, Srivastava SK, Wacher A, Turtle CJ, Kahsai O, Riddell SR, Warren EH, Carlson CS (2009) Comprehensive assessment of T-cell receptor beta-chain diversity in alphabeta T cells. Blood 114(19):4099–4107. doi: 10.1182/blood-2009-04-217604 CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Lossius A, Johansen JN, Vartdal F, Robins H, Jurate Saltyte B, Holmoy T, Olweus J (2014) High-throughput sequencing of TCR repertoires in multiple sclerosis reveals intrathecal enrichment of EBV-reactive CD8+ T cells. Eur J Immunol 44(11):3439–3452. doi: 10.1002/eji.201444662 CrossRefPubMedGoogle Scholar
- 30.Epstein-Barr virus-associated lymphoproliferative disorders*.Google Scholar
- 32.Silins SL, Sherritt MA, Silleri JM, Cross SM, Elliott SL, Bharadwaj M, Le TT, Morrison LE, Khanna R, Moss DJ, Suhrbier A, Misko IS (2001) Asymptomatic primary Epstein-Barr virus infection occurs in the absence of blood T-cell repertoire perturbations despite high levels of systemic viral load. Blood 98(13):3739–3744CrossRefPubMedGoogle Scholar
- 33.Misko IS, Cross SM, Khanna R, Elliott SL, Schmidt C, Pye SJ, Silins SL (1999) Crossreactive recognition of viral, self, and bacterial peptide ligands by human class I-restricted cytotoxic T lymphocyte clonotypes: implications for molecular mimicry in autoimmune disease. Proc Natl Acad Sci U S A 96(5):2279–2284CrossRefPubMedPubMedCentralGoogle Scholar
- 36.Kimura H, Tsuge I, Imai S, Yamamoto M, Kuzushima K, Osato T, Morishima T (1995) Intact antigen presentation for Epstein-Barr virus (EBV)-specific CTL by a lymphoblastoid cell line established from a patient with chronic active EBV infection. Med Microbiol Immunol 184(2):63–68CrossRefPubMedGoogle Scholar
- 38.van Dongen JJ, Langerak AW, Brüggemann M, Evans PA, Hummel M, Lavender FL, Delabesse E, Davi F, Schuuring E, García-Sanz R, van Krieken JH, Droese J, González D, Bastard C, White HE, Spaargaren M, González M, Parreira A, Smith JL, Morgan GJ, Kneba M, Macintyre EA (2003) Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia 17(12):2257–2317. doi: 10.1038/sj.leu.2403202 CrossRefPubMedGoogle Scholar
- 39.Ahn JS, Rew SY, Shin MG, Kim HR, Yang DH, Cho D, Kim SH, Bae SY, Lee SR, Kim YK, Kim HJ, Lee JJ (2010) Clinical significance of clonality and Epstein-Barr virus infection in adult patients with hemophagocytic lymphohistiocytosis. Am J Hematol 85(9):719–722. doi: 10.1002/ajh.21795 CrossRefPubMedGoogle Scholar
- 40.Langerak AW, Molina TJ, Lavender FL, Pearson D, Flohr T, Sambade C, Schuuring E, Al Saati T, van Dongen JJ, van Krieken JH (2007) Polymerase chain reaction-based clonality testing in tissue samples with reactive lymphoproliferations: usefulness and pitfalls. A report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia 21(2):222–229. doi: 10.1038/sj.leu.2404482 CrossRefPubMedGoogle Scholar
- 44.Koning D, Costa AI, Hoof I, Miles JJ, Nanlohy NM, Ladell K, Matthews KK, Venturi V, Schellens IM, Borghans JA, Kesmir C, Price DA, van Baarle D (2013) CD8+ TCR repertoire formation is guided primarily by the peptide component of the antigenic complex. J Immunol 190(3):931–939. doi: 10.4049/jimmunol.1202466 CrossRefPubMedGoogle Scholar