Impaired CD4+ Cytotoxic T Lymphocyte Activity in Polyomavirus BK Infected Kidney Transplant Recipients
,
Abstract
The reactivation of polyomavirus BK (BKPyV) contributes to increased morbidity and mortality rates of transplant patients, especially kidney transplant recipients (KTRs). CD4+ T cells are important immune cells active during BKPyV infection in KTRs. This research tried to examine the phenotype of CD4+ T cells in the stage of BKPyV activation in KTRs.The re
cipients were separated into 2 groups of BKPyV-active and nonactive KTRs (10 patients in each group) and were compared with 10 healthy control subjects. The viral load was evaluated by Taq-man quantitative real-time PCR. The frequency of different CD4+ T cell subsets was determined by analyzing markers such as CD45RO, CCR7, CD27, CD107a, perforin, and granzyme B using flow cytometry. The gene expression levels of transcription factors, including TBX21, GATA3, STAT3, and STAT6, contributing to CD4+ T cell activation, were also assessed.
A significantly higher proportion in CCR7+CD27+CD45RO-CD4+ T cell (naive Tcell) subsets was detected in BKPyV-active KTRs compared to nonactive ones. A significant increase was detected in the frequency of CD107a+, perforin+, and granzyme B+ CD4+ T cells in the BKPyV-active group compared to the nonactive group. In CD4+ T cells of KTRs, the mRNA expression of TBX21 and GATA3 was significantly increased in KTRs without BKPyV reactivation compared to BKPyV-active ones.
This investigation focused on the CD4+ T cell as an immunodominant T cell type with potential cytotoxicity. Based on these results, BKPyV may have a direct influence on the repertoire of CD4+ T cell subsets. Particularly, cytotoxic CD4+ T cells need further investigation to be considered as a therapeutic approach for BKPyV infection.
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2. Kariminik A, Yaghobi R, Dabiri S. CXCL9 expression and polyomavirus BK infectivity in renal transplant patients with nephropathy. Cell Mol Biol. 2016;62(1):104-8.
3. Cohen-Bucay A, Ramirez S, Gordon CE, Francis JM, Chitalia V. Advances in BK Virus Complications in Organ Transplantation and Beyond. Kidney Medicine. 2020.
4. Ledford RM, Patel NR, Demenczuk TM, Watanyar A, Herbertz T, Collett MS, et al. VP1 sequencing of all human rhinovirus serotypes: insights into genus phylogeny and susceptibility to antiviral capsid-binding compounds. J Virol. 2004;78(7):3663-74.
5. Funahashi Y. BK Virus-Associated Nephropathy after Renal Transplantation. Pathogens. 2021;10(2):150.
6. Foroudi MR, Yaghobi R, Afshari A, Roozbeh J, Miresmaeili SM, Javid A. The effect of BK polyomavirus large T antigen on CD4 and CD8 T cells in kidney transplant recipients. Transplant Immunol. 2022;74:101655.
7. Krymskaya L, Sharma MC, Martinez J, Haq W, Huang EC, Limaye AP, et al. Cross-reactivity of T lymphocytes recognizing a human cytotoxic T-lymphocyte epitope within BK and JC virus VP1 polypeptides. J Virol. 2005;79(17):11170-8.
8. Bohl DL, Brennan DC. BK virus nephropathy and kidney transplantation. Clin J Am Society Nephrol. 2007;2(Supplement 1):S36-S46.
9. Weist B, Schmueck M, Fuehrer H, Sattler A, Reinke P, Babel N. The role of CD4+ T cells in BKV-specific T cell immunity. Med Microbiol Immunol. 2014;203(6):395-408.
10. Dakroub F, Touzé A, Akl H, Brochot E. Pre-transplantation assessment of BK virus serostatus: significance, current methods, and obstacles. Viruses. 2019;11(10):945.
11. Azar MM, Assi R, Valika AK, Banach DB, Hall IE, Landry M-L, et al. Graft loss among renal-transplant recipients with early reduction of immunosuppression for BK viremia. World J Transplant. 2017;7(5):269.
12. Cukuranovic J, Ugrenovic S, Jovanovic I, Visnjic M, Stefanovic V. Viral infection in renal transplant recipients. Sci World J. 2012;2012.
13. Bruminhent J, Srisala S, Klinmalai C, Pinsai S, Watcharananan SP, Kantachuvesiri S, et al. BK Polyomavirus-specific T cell immune responses in kidney transplant recipients diagnosed with BK Polyomavirus-associated nephropathy. BMC Infect Dis. 2019;19(1):1-8.
14. Rahimi Z, Yaghobi R, Afshari A, Roozbeh J, Mokhtari MJ, Hosseini AM. The effect of BKV reactivation on cytokines behavior in kidney transplanted patients. BMC nephrol. 2022;23(1):1-11.
15. Espada E, Cheng MP, Kim HT, Woolley AE, Avigan JI, Forcade E, et al. BK virus–specific T-cell immune reconstitution after allogeneic hematopoietic cell transplantation. Blood advances. 2020;4(9):1881-93.
16. Rahimi Z, Yaghobi R, Afshari A, Roozbeh J, Mokhtari MJ, Hosseini AM. The effect of BKV reactivation on cytokines behavior in kidney transplanted patients. BMC nephrol. 2022;23(1):20.
17. Ambalathingal GR, Francis RS, Smyth MJ, Smith C, Khanna R. BK polyomavirus: clinical aspects, immune regulation, and emerging therapies. Clin Microbiol Rev. 2017;30(2):503-28.
18. Dillon SM, Mickens KL, Thompson TA, Cooper EH, Nesladek S, Christians AJ, et al. Granzyme B+ CD4 T cells accumulate in the colon during chronic HIV-1 infection. Gut Microbes. 2022;14(1):2045852.
19. Ambalathingal GR, Francis RS, Corvino D, Srihari S, Aftab BT, Smith C, et al. Proteome‐wide analysis of T‐cell response to BK polyomavirus in healthy virus carriers and kidney transplant recipients reveals a unique transcriptional and functional profile. Clin Trans Immunol. 2020;9(1):e01102.
20. Kanhere A, Hertweck A, Bhatia U, Gökmen MR, Perucha E, Jackson I, et al. T-bet and GATA3 orchestrate Th1 and Th2 differentiation through lineage-specific targeting of distal regulatory elements. Nat Communications. 2012;3(1):1-12.
21. Kariminik A, Yaghobi R, Dabiri S. Innate immunity and BK virus: prospective strategies. Viral Immunol. 2016;29(2):74-82.
22. Zareei N, Miri HR, Karimi MH, Afshari A, Geramizadeh B, Roozbeh J, et al. Increasing of the interferon-γ gene expression during polyomavirus BK infection in kidney transplant patients. Microbial pathogenesis. 2019;129:187-94.
23. Stervbo U, Nienen M, Weist BJ, Kuchenbecker L, Hecht J, Wehler P, et al. BKV clearance time correlates with exhaustion state and T-cell receptor repertoire shape of BKV-specific T-cells in renal transplant patients. Front Immunol. 2019;10:767.
24. Zaunders JJ, Dyer WB, Wang B, Munier ML, Miranda-Saksena M, Newton R, et al. Identification of circulating antigen-specific CD4+ T lymphocytes with a CCR5+, cytotoxic phenotype in an HIV-1 long-term nonprogressor and in CMV infection. Blood. 2004;103(6):2238-47.
25. Appay V, Zaunders JJ, Papagno L, Sutton J, Jaramillo A, Waters A, et al. Characterization of CD4+ CTLs ex vivo. J Immunol. 2002;168(11):5954-8.
26. Zhou W, Sharma M, Martinez J, Srivastava T, Diamond DJ, Knowles W, et al. Functional characterization of BK virus-specific CD4+ T cells with cytotoxic potential in seropositive adults. Viral Immunol. 2007;20(3):379-88.
27. Comoli P, Schilham MW, Basso S, Van Vreeswijk T, Bernardo ME, Maccario R, et al. T-cell lines specific for peptides of adenovirus hexon protein and devoid of alloreactivity against recipient cells can be obtained from HLA-haploidentical donors. J Immunotherapy. 2008;31(6):529-36.
28. Binggeli S, Egli A, Schaub S, Binet I, Mayr M, Steiger J, et al. Polyomavirus BK‐specific cellular immune response to VP1 and large T‐antigen in kidney transplant recipients. Am J Transplantation. 2007;7(5):1131-9.
29. Ahrends T, Busselaar J, Severson TM, Bąbała N, de Vries E, Bovens A, et al. CD4+ T cell help creates memory CD8+ T cells with innate and help-independent recall capacities. Nat Communications. 2019;10(1):5531.
30. Menter T, Mayr M, Schaub S, Mihatsch M, Hirsch H, Hopfer H. Pathology of resolving polyomavirus‐associated nephropathy. Am J Transplant. 2013;13(6):1474-83.
31. Intlekofer AM, Takemoto N, Wherry EJ, Longworth SA, Northrup JT, Palanivel VR, et al. Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat Immunol. 2005;6(12):1236-44.
32. Ho I-C, Tai T-S, Pai S-Y. GATA3 and the T-cell lineage: essential functions before and after T-helper-2-cell differentiation. Nat Rev Immunol. 2009;9(2):125-35.
33. Siegel A, Heimall J, Freeman A, Hsu A, Brittain E, Brenchley J, et al. A critical role for STAT3 transcription factor signaling in the development and maintenance of human T cell memory. Immunity. 2011;35(5):806-18.
34. King S, Knorn AM, Ohnmacht C, Voehringer D. Accumulation of effector CD4 T cells during type 2 immune responses is negatively regulated by Stat6. J Immunol. 2008;180(2):754-63.
35. Kao C, Oestreich KJ, Paley MA, Crawford A, Angelosanto JM, Ali M-AA, et al. Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8+ T cell responses during chronic infection. Nat Immunol. 2011;12(7):663-71.
36. Yoshida N, He F, Kyttaris VC. T cell–specific STAT3 deficiency abrogates lupus nephritis. Lupus. 2019;28(12):1468-72.
37. Yukawa K, Kishino M, Goda M, Liang X-M, Kimura A, Tanaka T, et al. STAT6 deficiency inhibits tubulointerstitial fibrosis in obstructive nephropathy. Int J Mol Med. 2005;15(2):225-30.
38. Yagi R, Junttila IS, Wei G, Urban Jr JF, Zhao K, Paul WE, et al. The transcription factor GATA3 actively represses RUNX3 protein-regulated production of interferon-γ. Immunity. 2010;32(4):507-17.
39. Messi M, Giacchetto I, Nagata K, Lanzavecchia A, Natoli G, Sallusto F. Memory and flexibility of cytokine gene expression as separable properties of human Th 1 and Th 2 lymphocytes. Nat Immunol. 2003;4(1):78-86.
40. O’Shea JJ, Paul WE. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science. 2010;327(5969):1098-102.
41. Sundrud MS, Grill SM, Ni D, Nagata K, Alkan SS, Subramaniam A, et al. Genetic reprogramming of primary human T cells reveals functional plasticity in Th cell differentiation. J Immunol. 2003;171(7):3542-9.
2. Kariminik A, Yaghobi R, Dabiri S. CXCL9 expression and polyomavirus BK infectivity in renal transplant patients with nephropathy. Cell Mol Biol. 2016;62(1):104-8.
3. Cohen-Bucay A, Ramirez S, Gordon CE, Francis JM, Chitalia V. Advances in BK Virus Complications in Organ Transplantation and Beyond. Kidney Medicine. 2020.
4. Ledford RM, Patel NR, Demenczuk TM, Watanyar A, Herbertz T, Collett MS, et al. VP1 sequencing of all human rhinovirus serotypes: insights into genus phylogeny and susceptibility to antiviral capsid-binding compounds. J Virol. 2004;78(7):3663-74.
5. Funahashi Y. BK Virus-Associated Nephropathy after Renal Transplantation. Pathogens. 2021;10(2):150.
6. Foroudi MR, Yaghobi R, Afshari A, Roozbeh J, Miresmaeili SM, Javid A. The effect of BK polyomavirus large T antigen on CD4 and CD8 T cells in kidney transplant recipients. Transplant Immunol. 2022;74:101655.
7. Krymskaya L, Sharma MC, Martinez J, Haq W, Huang EC, Limaye AP, et al. Cross-reactivity of T lymphocytes recognizing a human cytotoxic T-lymphocyte epitope within BK and JC virus VP1 polypeptides. J Virol. 2005;79(17):11170-8.
8. Bohl DL, Brennan DC. BK virus nephropathy and kidney transplantation. Clin J Am Society Nephrol. 2007;2(Supplement 1):S36-S46.
9. Weist B, Schmueck M, Fuehrer H, Sattler A, Reinke P, Babel N. The role of CD4+ T cells in BKV-specific T cell immunity. Med Microbiol Immunol. 2014;203(6):395-408.
10. Dakroub F, Touzé A, Akl H, Brochot E. Pre-transplantation assessment of BK virus serostatus: significance, current methods, and obstacles. Viruses. 2019;11(10):945.
11. Azar MM, Assi R, Valika AK, Banach DB, Hall IE, Landry M-L, et al. Graft loss among renal-transplant recipients with early reduction of immunosuppression for BK viremia. World J Transplant. 2017;7(5):269.
12. Cukuranovic J, Ugrenovic S, Jovanovic I, Visnjic M, Stefanovic V. Viral infection in renal transplant recipients. Sci World J. 2012;2012.
13. Bruminhent J, Srisala S, Klinmalai C, Pinsai S, Watcharananan SP, Kantachuvesiri S, et al. BK Polyomavirus-specific T cell immune responses in kidney transplant recipients diagnosed with BK Polyomavirus-associated nephropathy. BMC Infect Dis. 2019;19(1):1-8.
14. Rahimi Z, Yaghobi R, Afshari A, Roozbeh J, Mokhtari MJ, Hosseini AM. The effect of BKV reactivation on cytokines behavior in kidney transplanted patients. BMC nephrol. 2022;23(1):1-11.
15. Espada E, Cheng MP, Kim HT, Woolley AE, Avigan JI, Forcade E, et al. BK virus–specific T-cell immune reconstitution after allogeneic hematopoietic cell transplantation. Blood advances. 2020;4(9):1881-93.
16. Rahimi Z, Yaghobi R, Afshari A, Roozbeh J, Mokhtari MJ, Hosseini AM. The effect of BKV reactivation on cytokines behavior in kidney transplanted patients. BMC nephrol. 2022;23(1):20.
17. Ambalathingal GR, Francis RS, Smyth MJ, Smith C, Khanna R. BK polyomavirus: clinical aspects, immune regulation, and emerging therapies. Clin Microbiol Rev. 2017;30(2):503-28.
18. Dillon SM, Mickens KL, Thompson TA, Cooper EH, Nesladek S, Christians AJ, et al. Granzyme B+ CD4 T cells accumulate in the colon during chronic HIV-1 infection. Gut Microbes. 2022;14(1):2045852.
19. Ambalathingal GR, Francis RS, Corvino D, Srihari S, Aftab BT, Smith C, et al. Proteome‐wide analysis of T‐cell response to BK polyomavirus in healthy virus carriers and kidney transplant recipients reveals a unique transcriptional and functional profile. Clin Trans Immunol. 2020;9(1):e01102.
20. Kanhere A, Hertweck A, Bhatia U, Gökmen MR, Perucha E, Jackson I, et al. T-bet and GATA3 orchestrate Th1 and Th2 differentiation through lineage-specific targeting of distal regulatory elements. Nat Communications. 2012;3(1):1-12.
21. Kariminik A, Yaghobi R, Dabiri S. Innate immunity and BK virus: prospective strategies. Viral Immunol. 2016;29(2):74-82.
22. Zareei N, Miri HR, Karimi MH, Afshari A, Geramizadeh B, Roozbeh J, et al. Increasing of the interferon-γ gene expression during polyomavirus BK infection in kidney transplant patients. Microbial pathogenesis. 2019;129:187-94.
23. Stervbo U, Nienen M, Weist BJ, Kuchenbecker L, Hecht J, Wehler P, et al. BKV clearance time correlates with exhaustion state and T-cell receptor repertoire shape of BKV-specific T-cells in renal transplant patients. Front Immunol. 2019;10:767.
24. Zaunders JJ, Dyer WB, Wang B, Munier ML, Miranda-Saksena M, Newton R, et al. Identification of circulating antigen-specific CD4+ T lymphocytes with a CCR5+, cytotoxic phenotype in an HIV-1 long-term nonprogressor and in CMV infection. Blood. 2004;103(6):2238-47.
25. Appay V, Zaunders JJ, Papagno L, Sutton J, Jaramillo A, Waters A, et al. Characterization of CD4+ CTLs ex vivo. J Immunol. 2002;168(11):5954-8.
26. Zhou W, Sharma M, Martinez J, Srivastava T, Diamond DJ, Knowles W, et al. Functional characterization of BK virus-specific CD4+ T cells with cytotoxic potential in seropositive adults. Viral Immunol. 2007;20(3):379-88.
27. Comoli P, Schilham MW, Basso S, Van Vreeswijk T, Bernardo ME, Maccario R, et al. T-cell lines specific for peptides of adenovirus hexon protein and devoid of alloreactivity against recipient cells can be obtained from HLA-haploidentical donors. J Immunotherapy. 2008;31(6):529-36.
28. Binggeli S, Egli A, Schaub S, Binet I, Mayr M, Steiger J, et al. Polyomavirus BK‐specific cellular immune response to VP1 and large T‐antigen in kidney transplant recipients. Am J Transplantation. 2007;7(5):1131-9.
29. Ahrends T, Busselaar J, Severson TM, Bąbała N, de Vries E, Bovens A, et al. CD4+ T cell help creates memory CD8+ T cells with innate and help-independent recall capacities. Nat Communications. 2019;10(1):5531.
30. Menter T, Mayr M, Schaub S, Mihatsch M, Hirsch H, Hopfer H. Pathology of resolving polyomavirus‐associated nephropathy. Am J Transplant. 2013;13(6):1474-83.
31. Intlekofer AM, Takemoto N, Wherry EJ, Longworth SA, Northrup JT, Palanivel VR, et al. Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat Immunol. 2005;6(12):1236-44.
32. Ho I-C, Tai T-S, Pai S-Y. GATA3 and the T-cell lineage: essential functions before and after T-helper-2-cell differentiation. Nat Rev Immunol. 2009;9(2):125-35.
33. Siegel A, Heimall J, Freeman A, Hsu A, Brittain E, Brenchley J, et al. A critical role for STAT3 transcription factor signaling in the development and maintenance of human T cell memory. Immunity. 2011;35(5):806-18.
34. King S, Knorn AM, Ohnmacht C, Voehringer D. Accumulation of effector CD4 T cells during type 2 immune responses is negatively regulated by Stat6. J Immunol. 2008;180(2):754-63.
35. Kao C, Oestreich KJ, Paley MA, Crawford A, Angelosanto JM, Ali M-AA, et al. Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8+ T cell responses during chronic infection. Nat Immunol. 2011;12(7):663-71.
36. Yoshida N, He F, Kyttaris VC. T cell–specific STAT3 deficiency abrogates lupus nephritis. Lupus. 2019;28(12):1468-72.
37. Yukawa K, Kishino M, Goda M, Liang X-M, Kimura A, Tanaka T, et al. STAT6 deficiency inhibits tubulointerstitial fibrosis in obstructive nephropathy. Int J Mol Med. 2005;15(2):225-30.
38. Yagi R, Junttila IS, Wei G, Urban Jr JF, Zhao K, Paul WE, et al. The transcription factor GATA3 actively represses RUNX3 protein-regulated production of interferon-γ. Immunity. 2010;32(4):507-17.
39. Messi M, Giacchetto I, Nagata K, Lanzavecchia A, Natoli G, Sallusto F. Memory and flexibility of cytokine gene expression as separable properties of human Th 1 and Th 2 lymphocytes. Nat Immunol. 2003;4(1):78-86.
40. O’Shea JJ, Paul WE. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science. 2010;327(5969):1098-102.
41. Sundrud MS, Grill SM, Ni D, Nagata K, Alkan SS, Subramaniam A, et al. Genetic reprogramming of primary human T cells reveals functional plasticity in Th cell differentiation. J Immunol. 2003;171(7):3542-9.
| Files | ||
| Issue | Vol 22 No 4 (2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v22i4.13610 | |
| Keywords | ||
| CD4 positive T lymphocytes Cytotoxic Human polyomavirus BK Kidney transplantations T-lymphocytes | ||
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How to Cite
1.
Noshadi N, Yaghoubi R, Afshari A, Forouzanfar M, soleimanian S. Impaired CD4+ Cytotoxic T Lymphocyte Activity in Polyomavirus BK Infected Kidney Transplant Recipients. Iran J Allergy Asthma Immunol. 2023;22(4):379-389.
