Immunomodulatory Role of Combined BK Polyomavirus Small and Large T Antigens on CD4⁺ T Cell Subset Function and Differentiation in Kidney Transplant Recipients
-
Zahra Rasouli
,
Maryam Rahimi Foroudi
,
Afsoon Afshari
,
Amaneh Javid
,
Seyed Mohsen Miresmaeili
,
Mahdi Golshan
,
Ramin Yaghobi
Abstract
BK polyomavirus (BKPyV) reactivation is a major cause of allograft dysfunction and BKPyV-associated nephropathy (BKPyVAN) in kidney transplant recipients (KTRs). Although CD4⁺ T-cell responses are considered important for viral control, the immunomodulatory effects of BKPyV small T antigen (ST-Ag) remain poorly understood. This study investigated the effects of ST-Ag alone and combined large T antigen (LT-Ag)/ST-Ag stimulation on CD4⁺ T-cell differentiation and function in KTRs.
Peripheral blood mononuclear cells (PBMCs) from 10 KTRs and five healthy controls were stimulated with ST-Ag alone or a combined LT-Ag/ST-Ag peptide pool. Naive, central memory, and effector memory CD4⁺ T-cell subsets were analyzed by flow cytometry using CCR7, CD45RO, CD107a, and granzyme B. Expression of T-bet, GATA3, STAT3, STAT6, and perforin was quantified by real-time PCR.
Combined LT-Ag/ST-Ag stimulation was associated with a higher frequency of naive CD4⁺ T cells and lower frequencies of central and effector memory subsets in BKPyV-reactivated KTRs compared with BKPyV-negative recipients. Expression of T-bet, GATA3, STAT3, and STAT6 was significantly reduced, whereas perforin expression was increased. These findings are consistent with altered CD4⁺ T-cell differentiation in BKPyV-reactivated recipients.
BKPyV ST-Ag may contribute to altered CD4⁺ T-cell differentiation and immune dysregulation during viral reactivation. These findings provide preliminary insight into immune alterations associated with BKPyV reactivation and warrant validation in larger, independent cohorts.
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3. Yaghobi R, Afshari A, Roozbeh J. Host and viral RNA dysregulation during BK polyomavirus infection in kidney transplant recipients. Wiley Interdisciplinary Reviews: RNA. 2023;14(4):e1769.
4. Korup-Schulz S-V, Lucke C, Moens U, Schmuck R, Ehlers B. Large T antigen variants of human polyomaviruses 9 and 12 and seroreactivity against their N terminus. J General Virol. 2017;98(4):704–14.
5. Moens U, Macdonald A. Effect of the large and small T-antigens of human polyomaviruses on signaling pathways. Int J Mol Sci. 2019;20(16):3914.
6. Kariminik A, Yaghobi R, Dabiri S. Innate immunity and BK virus: prospective strategies. Viral Immunol. 2016;29(2):74–82.
7. Makvandi M, Kaydani GA, Shahbazian H, Teimoori A, Rahim F, Aslani S. The complete genome sequence BK polyomavirus study in kidney transplanted patients. J Nephropathol. 2019;8(2):1.
8. Levican J, Acevedo M, León O, Gaggero A, Aguayo F. Role of BK human polyomavirus in cancer. Infect Agent Cancer. 2018;13(1):12.
9. Sahragard I, Mohammadi A, Yaghobi R, Pakfetrat M, Afshari A, Sharifi H, et al. The relation of NCCR variations and host transcription factors gene regulation in BK polyomavirus infected kidney transplant patients. Gene. 2023;878:147567.
10. 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.
11. Randhawa P, Bohl D, Brennan D, Ruppert K, Ramaswami B, Storch G, et al. Longitudinal analysis of levels of immunoglobulins against BK virus capsid proteins in kidney transplant recipients. Clin Vaccine Immunol. 2008;15(10):1564–71.
12. Kausar A, Amraiz D, Ali L, Fatima M. A systematic review of BK and JC polyomaviruses in Asia: molecular insights and prevalence. Rev Med Virol. 2025;35(4):e70048.
13. 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.
14. Kariminik A, Dabiri S, Yaghobi R. Polyomavirus BK induces inflammation via up-regulation of CXCL10 at translation levels in renal transplant patients with nephropathy. Inflammation. 2016;39(4):1514–9.
15. Shakiba E, Yaghobi R, Ramzi M. Prevalence of viral infections and hemorrhagic cystitis in hematopoietic stem cell transplant recipients. Exp Clin Transplant. 2011;9(6):405–12.
16. 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.
17. Hirsch HH, Knowles W, Dickenmann M, Passweg J, Klimkait T, Mihatsch MJ, et al. Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients. New Eng J of Med. 2002;347(7):488–96.
18. Ginevri F, Azzi A, Hirsch H, Basso S, Fontana I, Cioni M, et al. Prospective monitoring of polyomavirus BK replication and impact of pre-emptive intervention in pediatric kidney recipients. Am J Transplant. 2007;7(12):2727–35.
19. Rahimi Foroudi M, Yaghobi R, Afshari A, Roozbeh J. Cancer Inducing Role of BK Polyomavirus Large T Antigen: Molecular Signaling View. Cancer Invest. 2026;44(4):427–43.
20. Park S, Anderson NL, Canaria DA, Olson MR. Granzyme-producing CD4 T cells in cancer and autoimmune disease. Immunohorizons. 2021;5(12):909–17.
21. Comoli P, Azzi A, Maccario R, Basso S, Botti G, Basile G, et al. Polyomavirus BK-specific immunity after kidney transplantation. Transplantation. 2004;78(8):1229–32.
22. Comoli P, Cioni M, Basso S, Gagliardone C, Potenza L, Verrina E, et al. Immunity to polyomavirus BK infection: immune monitoring to regulate the balance between risk of BKV nephropathy and induction of alloimmunity. J Immunol Res. 2013;2013(1):256923.
23. 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 Adv. 2020;4(9):1881–93.
24. Chakera A, Bennett S, Lawrence S, Morteau O, Mason P, O'Callaghan C, et al. Antigen-specific T cell responses to BK polyomavirus antigens identify functional anti-viral immunity and may help to guide immunosuppression following renal transplantation. Clini Exp Immunol. 2011;165(3):401–9.
25. Schmidt T, Adam C, Hirsch H, Janssen M, Wolf M, Dirks J, et al. BK polyomavirus‐specific cellular immune responses are age‐dependent and strongly correlate with phases of virus replication. Am J Transplant. 2014;14(6):1334–45.
26. Shen C-L, Wu B-S, Lien T-J, Yang A-H, Yang C-Y. BK polyomavirus nephropathy in kidney transplantation: balancing rejection and infection. Viruses. 2021;13(3):487.
27. 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. Fron Immunol. 2019;10:767.
28. Weist BJ, Wehler P, El Ahmad L, Schmueck-Henneresse M, Millward JM, Nienen M, et al. A revised strategy for monitoring BKV-specific cellular immunity in kidney transplant patients. Kidney Int. 2015;88(6):1293–303.
29. Blyth E, Clancy L, Simms R, Gaundar S, O'Connell P, Micklethwaite K, et al. BK virus-specific T cells for use in cellular therapy show specificity to multiple antigens and polyfunctional cytokine responses. Transplantation. 2011;92(10):1077–84.
30. 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.
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. Tamachi T, Takatori H, Fujiwara M, Hirose K, Maezawa Y, Kagami S-i, et al. STAT6 inhibits T-bet-independent Th1 cell differentiation. Biochem Biophys Res Commun. 2009;382(4):751–5.
33. Yagi R, Junttila IS, Wei G, Urban JF, Zhao K, Paul WE, et al. The transcription factor GATA33 actively represses RUNX3 protein-regulated production of interferon-γ.Immunity. 2010;32(4):507–17.
34. Messi M, Giacchetto I, Nagata K, Lanzavecchia A, Natoli G, Sallusto F. Memory and flexibility of cytokine gene expression as separable properties of human TH1 and TH2 lymphocytes. Nature Immunol. 2003;4(1):78–86.
35. O’Shea JJ, Paul WE. Mechanisms underlying lineage commitment and plasticity of helper CD4⁺ T cells. Science. 2010;327(5969):1098–102.
36. Sundrud MS, Grill SM, Ni D, Nagata t 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.
37. Gai L, Zhu Y, Zhang C, Meng X. Targeting canonical and non-canonical STAT signaling pathways in renal diseases. Cells. 2021;10(7):1610.
38. Yoshida N, He F, Kyttaris VC. T cell–specific STAT3 deficiency abrogates lupus nephritis. Lupus. 2019;28(12):1468–72.
39. Jöhrens K, Anagnostopoulos I, Dürkop H, Stein H. Different T‐bet expression patterns characterize particular reactive lymphoid tissue lesions. Histopathology. 2006;48(4):343–52.
40. Knox JJ, Kaplan DE, Betts MR. T-bet-expressing B cells during HIV and HCV infections. Cell Immunol. 2017;321:26–34.
41. Li Y, Zhou Y, Shu S, Zhu D, Yang Z, Fang F. Effects of acute and chronic murine cytomegalovirus infections on the ratio of regulatory T cells and expression of Th1/Th2 transcription factors T-bet/GATA3.Zhonghua yi xue za zhi. 2008;88(42):2999–3002.
42. Odetola OE, Isaila B, Pambuccian SE, Barkan GA. Unusual BK polyomavirus‐associated urologic malignancies in renal transplant recipients: Report of two cases and review of the literature. Diagnostic Cytopathol. 2018;46(12):1050–9.
43. Schneidewind L, Neumann T, Krüger W, Hakenberg OW, Schmidt CA. Targeting IL‐11 in the treatment of BK virus‐associated haemorrhagic cystitis—A promising new approach. J Cell Molecular Med. 2020;24(16):9097–100.
44. Chen H, Sun H, You F, Sun W, Zhou X, Chen L, et al. Activation of STAT6 by STING is critical for antiviral innate immunity. Cell. 2011;147(2):436–46.
45. Kant S, Dasgupta A, Bagnasco S, Brennan DC. BK virus nephropathy in kidney transplantation: a state-of-the-art review. Viruses. 2022;14(8):1616.
2. Foroudi MR, Yaghobi R, Afshari A, Roozbeh J, Miresmaeili SM, Javid A. The effect of the BK polyomavirus large T antigen on the function and maturity of the CD4⁺ T cell subsets in kidney transplant recipients. Transplant Immunol. 2023;80:101884.
3. Yaghobi R, Afshari A, Roozbeh J. Host and viral RNA dysregulation during BK polyomavirus infection in kidney transplant recipients. Wiley Interdisciplinary Reviews: RNA. 2023;14(4):e1769.
4. Korup-Schulz S-V, Lucke C, Moens U, Schmuck R, Ehlers B. Large T antigen variants of human polyomaviruses 9 and 12 and seroreactivity against their N terminus. J General Virol. 2017;98(4):704–14.
5. Moens U, Macdonald A. Effect of the large and small T-antigens of human polyomaviruses on signaling pathways. Int J Mol Sci. 2019;20(16):3914.
6. Kariminik A, Yaghobi R, Dabiri S. Innate immunity and BK virus: prospective strategies. Viral Immunol. 2016;29(2):74–82.
7. Makvandi M, Kaydani GA, Shahbazian H, Teimoori A, Rahim F, Aslani S. The complete genome sequence BK polyomavirus study in kidney transplanted patients. J Nephropathol. 2019;8(2):1.
8. Levican J, Acevedo M, León O, Gaggero A, Aguayo F. Role of BK human polyomavirus in cancer. Infect Agent Cancer. 2018;13(1):12.
9. Sahragard I, Mohammadi A, Yaghobi R, Pakfetrat M, Afshari A, Sharifi H, et al. The relation of NCCR variations and host transcription factors gene regulation in BK polyomavirus infected kidney transplant patients. Gene. 2023;878:147567.
10. 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.
11. Randhawa P, Bohl D, Brennan D, Ruppert K, Ramaswami B, Storch G, et al. Longitudinal analysis of levels of immunoglobulins against BK virus capsid proteins in kidney transplant recipients. Clin Vaccine Immunol. 2008;15(10):1564–71.
12. Kausar A, Amraiz D, Ali L, Fatima M. A systematic review of BK and JC polyomaviruses in Asia: molecular insights and prevalence. Rev Med Virol. 2025;35(4):e70048.
13. 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.
14. Kariminik A, Dabiri S, Yaghobi R. Polyomavirus BK induces inflammation via up-regulation of CXCL10 at translation levels in renal transplant patients with nephropathy. Inflammation. 2016;39(4):1514–9.
15. Shakiba E, Yaghobi R, Ramzi M. Prevalence of viral infections and hemorrhagic cystitis in hematopoietic stem cell transplant recipients. Exp Clin Transplant. 2011;9(6):405–12.
16. 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.
17. Hirsch HH, Knowles W, Dickenmann M, Passweg J, Klimkait T, Mihatsch MJ, et al. Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients. New Eng J of Med. 2002;347(7):488–96.
18. Ginevri F, Azzi A, Hirsch H, Basso S, Fontana I, Cioni M, et al. Prospective monitoring of polyomavirus BK replication and impact of pre-emptive intervention in pediatric kidney recipients. Am J Transplant. 2007;7(12):2727–35.
19. Rahimi Foroudi M, Yaghobi R, Afshari A, Roozbeh J. Cancer Inducing Role of BK Polyomavirus Large T Antigen: Molecular Signaling View. Cancer Invest. 2026;44(4):427–43.
20. Park S, Anderson NL, Canaria DA, Olson MR. Granzyme-producing CD4 T cells in cancer and autoimmune disease. Immunohorizons. 2021;5(12):909–17.
21. Comoli P, Azzi A, Maccario R, Basso S, Botti G, Basile G, et al. Polyomavirus BK-specific immunity after kidney transplantation. Transplantation. 2004;78(8):1229–32.
22. Comoli P, Cioni M, Basso S, Gagliardone C, Potenza L, Verrina E, et al. Immunity to polyomavirus BK infection: immune monitoring to regulate the balance between risk of BKV nephropathy and induction of alloimmunity. J Immunol Res. 2013;2013(1):256923.
23. 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 Adv. 2020;4(9):1881–93.
24. Chakera A, Bennett S, Lawrence S, Morteau O, Mason P, O'Callaghan C, et al. Antigen-specific T cell responses to BK polyomavirus antigens identify functional anti-viral immunity and may help to guide immunosuppression following renal transplantation. Clini Exp Immunol. 2011;165(3):401–9.
25. Schmidt T, Adam C, Hirsch H, Janssen M, Wolf M, Dirks J, et al. BK polyomavirus‐specific cellular immune responses are age‐dependent and strongly correlate with phases of virus replication. Am J Transplant. 2014;14(6):1334–45.
26. Shen C-L, Wu B-S, Lien T-J, Yang A-H, Yang C-Y. BK polyomavirus nephropathy in kidney transplantation: balancing rejection and infection. Viruses. 2021;13(3):487.
27. 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. Fron Immunol. 2019;10:767.
28. Weist BJ, Wehler P, El Ahmad L, Schmueck-Henneresse M, Millward JM, Nienen M, et al. A revised strategy for monitoring BKV-specific cellular immunity in kidney transplant patients. Kidney Int. 2015;88(6):1293–303.
29. Blyth E, Clancy L, Simms R, Gaundar S, O'Connell P, Micklethwaite K, et al. BK virus-specific T cells for use in cellular therapy show specificity to multiple antigens and polyfunctional cytokine responses. Transplantation. 2011;92(10):1077–84.
30. 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.
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. Tamachi T, Takatori H, Fujiwara M, Hirose K, Maezawa Y, Kagami S-i, et al. STAT6 inhibits T-bet-independent Th1 cell differentiation. Biochem Biophys Res Commun. 2009;382(4):751–5.
33. Yagi R, Junttila IS, Wei G, Urban JF, Zhao K, Paul WE, et al. The transcription factor GATA33 actively represses RUNX3 protein-regulated production of interferon-γ.Immunity. 2010;32(4):507–17.
34. Messi M, Giacchetto I, Nagata K, Lanzavecchia A, Natoli G, Sallusto F. Memory and flexibility of cytokine gene expression as separable properties of human TH1 and TH2 lymphocytes. Nature Immunol. 2003;4(1):78–86.
35. O’Shea JJ, Paul WE. Mechanisms underlying lineage commitment and plasticity of helper CD4⁺ T cells. Science. 2010;327(5969):1098–102.
36. Sundrud MS, Grill SM, Ni D, Nagata t 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.
37. Gai L, Zhu Y, Zhang C, Meng X. Targeting canonical and non-canonical STAT signaling pathways in renal diseases. Cells. 2021;10(7):1610.
38. Yoshida N, He F, Kyttaris VC. T cell–specific STAT3 deficiency abrogates lupus nephritis. Lupus. 2019;28(12):1468–72.
39. Jöhrens K, Anagnostopoulos I, Dürkop H, Stein H. Different T‐bet expression patterns characterize particular reactive lymphoid tissue lesions. Histopathology. 2006;48(4):343–52.
40. Knox JJ, Kaplan DE, Betts MR. T-bet-expressing B cells during HIV and HCV infections. Cell Immunol. 2017;321:26–34.
41. Li Y, Zhou Y, Shu S, Zhu D, Yang Z, Fang F. Effects of acute and chronic murine cytomegalovirus infections on the ratio of regulatory T cells and expression of Th1/Th2 transcription factors T-bet/GATA3.Zhonghua yi xue za zhi. 2008;88(42):2999–3002.
42. Odetola OE, Isaila B, Pambuccian SE, Barkan GA. Unusual BK polyomavirus‐associated urologic malignancies in renal transplant recipients: Report of two cases and review of the literature. Diagnostic Cytopathol. 2018;46(12):1050–9.
43. Schneidewind L, Neumann T, Krüger W, Hakenberg OW, Schmidt CA. Targeting IL‐11 in the treatment of BK virus‐associated haemorrhagic cystitis—A promising new approach. J Cell Molecular Med. 2020;24(16):9097–100.
44. Chen H, Sun H, You F, Sun W, Zhou X, Chen L, et al. Activation of STAT6 by STING is critical for antiviral innate immunity. Cell. 2011;147(2):436–46.
45. Kant S, Dasgupta A, Bagnasco S, Brennan DC. BK virus nephropathy in kidney transplantation: a state-of-the-art review. Viruses. 2022;14(8):1616.
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How to Cite
1.
Rasouli Z, Rahimi Foroudi M, Afshari A, Javid A, Miresmaeili SM, Golshan M, Yaghobi R. Immunomodulatory Role of Combined BK Polyomavirus Small and Large T Antigens on CD4⁺ T Cell Subset Function and Differentiation in Kidney Transplant Recipients. Iran J Allergy Asthma Immunol. 2026;:1-13.
