Features of T Cell Receptor Repertoires of Influenza H7N9 Virus Infected Patients in Convalescence_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

HouDongni ¹ , HeFusheng ² , WangMingbang ³ , ChenCuicui ¹ , WangBaoqing ¹ ,  ZhouWenhao ³ ,  SongYuanlin ¹

1. Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China;
2. ;
3. ;

Corresponding author：

ZhouWenhao, Email: zwhchfu@126.com; SongYuanlin, Email: ylsong70@163.com

Keywords：

High-throughput sequencing; Immune repertoire; Complementary determining region; Bioinformatics; Avian influenza virus

DOI：

10.7507/1671-6205.2016102

Video：

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Objective To investigate specific changes of T cell repertoire in convalescent patients infected by influenza A (H7N9) virus. Methods Peripheral blood samples from 8 convalescent patients infected by H7N9 virus and 10 healthy donors were collected. After extracting whole DNA from these samples, arm-PCR were performed and the products were submitted to Illumina HiSeq2000 platform to produce deep sequencing data of the nucleotide sequences of complementary determining region 3 of T cell receptor β chain (TRB). Differences were compared in TRB diversity and V-D-J gene usage and similarities of sequences between the patients and the healthy donors. Results Frequency of V-D-J gene usage was different between the H7N9 patient group and the healthy group, such as TRBV30, TRBV27, and TRBV18 (Student's t test, P < 05). Main component analysis showed V-J pairing pattern was significantly different between two groups, which may have potential in identifying patients from healthy people. A considerable number of shared CDR3s were found in patient-patient pairs and normal-normal pairs, while seldom were found in patient-normal pairs. The similarity between patients was also confirmed by overlap distance analysis. Indexes for assessing diversity of immune repertoires, Shannon-Weiner index and Simpson index, were both lower in the patients (Student's t test, P < 05), suggesting that the immune system of the patients had not recovered 6 months after H7N9 infection. Compared with the healthy donors, the number of hyper-expression clones increased in the patient group, and some of them showed similarity among patients. Conclusions TRB repertoires are less diverse in patients with increased hyper-expressed clones and identifiable V-J usage pattern, which is identifiable from normal population. These results suggest that there are H7N9-specific changes in TRB repertoires of H7N9 infected patients in convalescent phase, which have potential implication in diagnosis and therapeutic T cell development.

Citation： Hou Dongni, He Fusheng, Wang Mingbang, Chen Cuicui, Wang Baoqing, Zhou Wenhao, Song Yuanlin. Features of T Cell Receptor Repertoires of Influenza H7N9 Virus Infected Patients in Convalescence. Chinese Journal of Respiratory and Critical Care Medicine, 2016, 15(5): 429-436. doi: 10.7507/1671-6205.2016102 Copy

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4.	Duvvuri VR, Duvvuri B, Alice C, et al.Preexisting CD4⁺ T-cell immunity in human population to avian influenza H7N9 virus:whole proteome-wide immunoinformatics analyses. PLoS One, 2014, 9:e91273.
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13.	Hughes MM, Yassai M, Sedy JR, et al. T cell receptor CDR3 loop length repertoire is determined primarily by features of the V(D)J recombination reaction. Eur J Immunol, 2003, 33:1568-1575.
14.	Miqueu P, Guillet M, Degauque N, et al.Statistical analysis of CDR3 length distributions for the assessment of T and B cell repertoire biases. Mol Immunol, 2007, 44:1057-1064.
15.	Strutt TM, McKinstry KK, Marshall NB, et al.Multipronged CD4⁺ T-cell effector and memory responses cooperate to provide potent immunity against respiratory virus. Immunol Rev, 2013, 255:149-164.
16.	Harty JT, Badovinac VP.Shaping and reshaping CD8⁺ T-cell memory. Nat Rev Immunol, 2008, 8:107-119.
17.	Badovinac VP, Porter BB, Harty JT.Programmed contraction of CD8⁺ T cells after infection. Nat Immunol, 2002, 3:619-626.
18.	Richards KA, Chaves FA, Sant AJ.The memory phase of the CD4 T-cell response to influenza virus infection maintains its diverse antigen specificity. Immunology, 2011, 133:246-256.
19.	Crotty S, Ahmed R.Immunological memory in humans. Semin Immunol, 2004, 16:197-203.
20.	Lewis SM.The mechanism of V(D)J joining:lessons from molecular, immunological, and comparative analyses. Adv Immunol, 1994, 56:27-150.
21.	Yang J, Chen J, Mao H, et al.Skewed T-cell receptor beta chain variable gene (TCRBV) usage among different clinical types of patients with chronic HBV infection. FEMS Immunol Med Microbiol, 2012, 65:448-455.
22.	Marrero I, Hamm DE, Davies JD.High-throughput sequencing of islet-infiltrating memory CD4⁺ T cells reveals a similar pattern of TCR Vbeta usage in prediabetic and diabetic NOD mice. PLoS One, 2013, 8:e76546.
23.	Costa AI, Koning D, Ladell K, et al.Complex T-cell receptor repertoire dynamics underlie the CD8⁺ T-cell response to HIV-1. J Virol, 2 015, 89:110-119.
24.	Turner SJ, La Gruta NL, Kedzierska K, et al.Functional implications of T cell receptor diversity. Curr Opin Immunol, 2009, 21:286-290.
25.	Jost L.Partitioning diversity into independent alpha and beta components. Ecology, 2007, 88:2427-2439.
26.	Birnbaum ME, Dong S, Garcia KC.Diversity-oriented approaches for interrogating T-cell receptor repertoire, ligand recognition, and function. Immunol Rev, 2012, 250:82-101.
27.	Goronzy JJ, Weyand CM.T cell development and receptor diversity during aging. Curr Opin Immunol, 2005, 17:468-475.
28.	Goronzy JJ, Lee WW, Weyand CM.Aging and T-cell diversity. Exp Gerontol, 2007, 42:400-406.
29.	Yager EJ, Ahmed M, Lanzer K, et al.Age-associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus. J Exp Med, 2008, 205:711-723.
30.	Lanzer KG, Johnson LL, Woodland DL, et al.Impact of ageing on the response and repertoire of influenza virus-specific CD4 T cells. Immun Ageing, 2014, 11:9.

1. Gao R, Cao B, Hu Y, et al. Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med, 2013, 368:1888-1897.
2. Epstein SL.Prior H1N1 influenza infection and susceptibility of Cleveland Family Study participants during the H2N2 pandemic of 1957:an experiment of nature. J Infect Dis, 2006, 193:49-53.
3. Sridhar S, Begom S, Bermingham A, et al.Cellular immune correlates of protection against symptomatic pandemic influenza. Nat Med, 2013, 19:1305-1312.
4. Duvvuri VR, Duvvuri B, Alice C, et al.Preexisting CD4⁺ T-cell immunity in human population to avian influenza H7N9 virus:whole proteome-wide immunoinformatics analyses. PLoS One, 2014, 9:e91273.
5. Quinones-Parra S, Grant E, Loh L, et al.Preexisting CD8⁺ T-cell immunity to the H7N9 influenza A virus varies across ethnicities. Proc Natl Acad Sci U S A, 2014, 111:1049-1054.
6. van de Sandt CE, Kreijtz JH, de Mutsert G, et al.Human cytotoxic T lymphocytes directed to seasonal influenza A viruses cross-react with the newly emerging H7N9 virus. J Virol, 2014, 88:1684-1693.
7. Wang Z, Wan Y, Qiu C, et al.Recovery from severe H7N9 disease is associated with diverse response mechanisms dominated by CD8⁺ T cells. Nat Commun, 2015, 6:6833.
8. La Gruta NL, Turner SJ.T cell mediated immunity to influenza:mechanisms of viral control. Trends Immunol, 2014, 35:396-402.
9. Zhang W, Du Y, Su Z, et al.IMonitor:A Robust Pipeline for TCR and BCR repertoire analysis. Genetics, 2015, 201:459-472.
10. Messaoudi I, Guevara-Patino JA, Dyall R, et al.Direct link between mhc polymorphism, T cell avidity, and diversity in immune defense. Science, 2002, 298:1797-1800.
11. Gearhart PJ.Immunology:the roots of antibody diversity. Nature, 2002, 419:29-31.
12. Brawand P, Cerottini JC, MacDonald HR.Hierarchal utilization of different T-cell receptor Vbeta gene segments in the CD8⁺-T-cell response to an immunodominant Moloney leukemia virus-encoded epitope in vivo. J Virol, 1999, 73:9161-9169.
13. Hughes MM, Yassai M, Sedy JR, et al. T cell receptor CDR3 loop length repertoire is determined primarily by features of the V(D)J recombination reaction. Eur J Immunol, 2003, 33:1568-1575.
14. Miqueu P, Guillet M, Degauque N, et al.Statistical analysis of CDR3 length distributions for the assessment of T and B cell repertoire biases. Mol Immunol, 2007, 44:1057-1064.
15. Strutt TM, McKinstry KK, Marshall NB, et al.Multipronged CD4⁺ T-cell effector and memory responses cooperate to provide potent immunity against respiratory virus. Immunol Rev, 2013, 255:149-164.
16. Harty JT, Badovinac VP.Shaping and reshaping CD8⁺ T-cell memory. Nat Rev Immunol, 2008, 8:107-119.
17. Badovinac VP, Porter BB, Harty JT.Programmed contraction of CD8⁺ T cells after infection. Nat Immunol, 2002, 3:619-626.
18. Richards KA, Chaves FA, Sant AJ.The memory phase of the CD4 T-cell response to influenza virus infection maintains its diverse antigen specificity. Immunology, 2011, 133:246-256.
19. Crotty S, Ahmed R.Immunological memory in humans. Semin Immunol, 2004, 16:197-203.
20. Lewis SM.The mechanism of V(D)J joining:lessons from molecular, immunological, and comparative analyses. Adv Immunol, 1994, 56:27-150.
21. Yang J, Chen J, Mao H, et al.Skewed T-cell receptor beta chain variable gene (TCRBV) usage among different clinical types of patients with chronic HBV infection. FEMS Immunol Med Microbiol, 2012, 65:448-455.
22. Marrero I, Hamm DE, Davies JD.High-throughput sequencing of islet-infiltrating memory CD4⁺ T cells reveals a similar pattern of TCR Vbeta usage in prediabetic and diabetic NOD mice. PLoS One, 2013, 8:e76546.
23. Costa AI, Koning D, Ladell K, et al.Complex T-cell receptor repertoire dynamics underlie the CD8⁺ T-cell response to HIV-1. J Virol, 2 015, 89:110-119.
24. Turner SJ, La Gruta NL, Kedzierska K, et al.Functional implications of T cell receptor diversity. Curr Opin Immunol, 2009, 21:286-290.
25. Jost L.Partitioning diversity into independent alpha and beta components. Ecology, 2007, 88:2427-2439.
26. Birnbaum ME, Dong S, Garcia KC.Diversity-oriented approaches for interrogating T-cell receptor repertoire, ligand recognition, and function. Immunol Rev, 2012, 250:82-101.
27. Goronzy JJ, Weyand CM.T cell development and receptor diversity during aging. Curr Opin Immunol, 2005, 17:468-475.
28. Goronzy JJ, Lee WW, Weyand CM.Aging and T-cell diversity. Exp Gerontol, 2007, 42:400-406.
29. Yager EJ, Ahmed M, Lanzer K, et al.Age-associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus. J Exp Med, 2008, 205:711-723.
30. Lanzer KG, Johnson LL, Woodland DL, et al.Impact of ageing on the response and repertoire of influenza virus-specific CD4 T cells. Immun Ageing, 2014, 11:9.

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