Phenotyping of TH9 Cells in Cytomegalovirus-reactivated Kidney Transplant Recipients
,
Abstract
Human cytomegalovirus (HCMV) is a frequent complication in kidney transplant recipients (KTRs), often impacting immune regulation. TH9 cells, a subset of CD4+ T cells, are characterized by their secretion of interleukin-9 (IL-9). This study aimed to analyze the phenotypic profile of TH9 cells and their associated cytokine expression in KTRs, and to evaluate mRNA levels of IL-4 and transforming growth factor-β (TGF-β), key cytokines involved in TH9 differentiation.
Ten HCMV+ and 10 HCMV− KTRs, along with 10 age- and sex-matched healthy controls, were enrolled. HCMV viral load was quantified using TaqMan real-time polymerase chain reaction. Flow cytometry was used to assess surface markers (CCR6+CCR4−IL-4Rα+CD4+) and intracellular IL-9 expression in TH9 cells. Gene expression levels of IL-4 and TGF-β were also assessed.
Surface staining revealed a significantly higher frequency of CD4+CCR4− and CD4+CCR6+ T cells in HCMV− KTRs compared to HCMV+ patients. Conversely, the overall frequency of CD4+ TH9 cells was elevated in HCMV+ KTRs. Intracellular staining demonstrated a significant increase in CD4+IL-9+ and CD4+IL-4Rα+ T cells in the HCMV+ group. Additionally, mRNA expression levels of IL-4 and TGF-β were markedly higher in HCMV+ KTRs than in HCMV− counterparts.
These findings suggest a potential role for TH9 cells and their signature cytokine IL-9 in the antiviral immune response in KTRs. While TH9 cells may contribute to HCMV-related immune modulation, further research is needed to fully elucidate their protective mechanisms against viral infections.
Keywords: ; ; ;
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6. Soleimanian S, Yaghobi R, Karimi MH, Geramizadeh B, Roozbeh J, Aghdaie MH, et al. Circulating NKG2C+ NK cell expressing CD107a/LAMP-1 subsets at the onset of CMV reactivation in seropositive kidney transplant recipients. Transpl Immunol. 2021;69:101460.
7. Lilleri D, Zelini P, Fornara C, Zavaglio F, Rampino T, Perez L, et al. Human cytomegalovirus (HCMV)‐specific T cell but not neutralizing or IgG binding antibody responses to glycoprotein complexes gB, gHgLgO, and pUL128L correlate with protection against high HCMV viral load reactivation in solid‐organ transplant recipients. J Med Virol. 2018;90(10):1620-8.
8. Giménez E, Blanco-Lobo P, Munoz-Cobo B, Solano C, Amat P, Pérez-Romero P, et al. Role of cytomegalovirus (CMV)-specific polyfunctional CD8+ T-cells and antibodies neutralizing virus epithelial infection in the control of CMV infection in an allogeneic stem-cell transplantation setting. J Gen Virol. 2015;96(9):2822-31.
9. Gabanti E, Bruno F, Lilleri D, Fornara C, Zelini P, Cane I, et al. Human cytomegalovirus (HCMV)-specific CD4+ and CD8+ T cells are both required for prevention of HCMV disease in seropositive solid-organ transplant recipients. PLoS One. 2014;9(8):e106044.
10. Eyerich S, Eyerich K, Pennino D, Carbone T, Nasorri F, Pallotta S, et al. TH22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J Clin Invest. 2009;119(12):3573-85.
11. Mahnke YD, Beddall MH, Roederer M. OMIP-017: human CD4+ helper T-cell subsets including follicular helper cells. Cytometry A. 2013;83(5):439-40.
12. Luckheeram RV, Zhou R, Verma AD, Xia B. CD4+ T cells: differentiation and functions. Clin Dev Immunol. 2012;2012:925135.
13. Meesing A, Razonable RR. Pharmacologic and immunologic management of cytomegalovirus infection after solid organ and hematopoietic stem cell transplantation. Expert Rev Clin Pharmacol. 2018;11(8):773-88.
14. Jorgenson MR, Hillis MI, Saddler CM, Smith JA, Parajuli S, Mandelbrot DA, et al. Prediction of cytomegalovirus infection: a single-center experience utilizing a newly available cell-mediated immunity assay by flow cytometry, a risk factor screening tool, and serologically demonstrated immunity. Transpl Infect Dis. 2020;22(4):e13311.
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20. Duhen T, Duhen R, Lanzavecchia A, Sallusto F, Campbell DJ. Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector TH cells. Blood. 2012;119(19):4430-40.
21. Afshari A, Yaghobi R, Karimi MH, Darbouy M, Azarpira N, Geramizadeh B, et al. IL-17 mRNA expression and cytomegalovirus infection in liver transplant patients. Exp Clin Transplant. 2015;13(Suppl 1):83-9.
22. Räihä J, Ortiz F, Mannonen L, Loginov R, Lempinen M, Lautenschlager I, et al. The burden of cytomegalovirus infection remains high in high-risk kidney transplant recipients despite six-month valganciclovir prophylaxis. Transpl Infect Dis. 2021;23(4):e13577.
23. Jackson SE, Mason GM, Wills MR. Human cytomegalovirus immunity and immune evasion. Virus Res. 2011;157(2):151-60.
24. Pang N, Xu J, Qu J, Duan X, Yuan H, Chen G, et al. Peripheral blood TH9 cells reconstitution and its relationship with acute graft-versus-host disease after matched-sibling peripheral blood hematopoietic stem cell transplantation. Am J Transl Res. 2017;9(8):3623-34.
25. Chatterjee S, Clark CE, Lugli E, Roederer M, Nutman TB, et al. Filarial infection modulates the immune response to Mycobacterium tuberculosis through expansion of CD4+ IL-4 memory T cells. J Immunol. 2015;194(6):2706-14.
26. Poulin LF, Richard M, Le Moine A, Kiss R, McKenzie AN, Goldman M, et al. Interleukin-9 promotes eosinophilic rejection of mouse heart allografts. Transplantation. 2003;76(3):572-7.
27. Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Stevens S, Flavell RA, et al. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity. 2008;29(6):947-57.
28. Jabeen R, Kaplan MH. The symphony of the ninth: the development and function of TH9 cells. Curr Opin Immunol. 2012;24(3):303-7.
29. Manzardo A, Henkhaus R, Dhillon S, Butler M, et al. Plasma cytokine levels in children with autistic disorder and unrelated siblings. Int J Dev Neurosci. 2012;30(2):121-7.
30. Ali ME, El-Badawy O, Afifi NA, Eldin AS, Hassan EA, Halby HM, et al. Role of T-helper 9 cells in chronic hepatitis C-infected patients. Viruses. 2018;10(7):341.
31. Abdelhamid AE, Abdel Salam SA, Faheem HA, Ahmed OA, Salah MM, Aly HI, et al. Interleukin-9: investigating its possible role in liver cirrhosis progression and in tumour promotion of hepatocellular carcinoma in chronic HCV infected patients, a single centre study. Microb Infect Dis. 2021;2(2):260-70.
32. McNamara PS, Flanagan BF, Baldwin LM, Newland P, Hart CA, Smyth RL, et al. Interleukin 9 production in the lungs of infants with severe respiratory syncytial virus bronchiolitis. Lancet. 2004;363(9414):1031-7.
33. Guzmán-Fulgencio M, Jiménez JL, Berenguer J, Fernández-Rodríguez A, López JC, Cosín J, et al. Plasma IL-6 and IL-9 predict the failure of interferon-α plus ribavirin therapy in HIV/HCV-coinfected patients. J Antimicrob Chemother. 2012;67(5):1238-45.
34. Nowak EC, Noelle RJ. Interleukin-9 as a T helper type 17 cytokine. Immunology. 2010;131(2):169-73.
35. Bălănescu P, Lădaru A, Voiosu T, Nicolau A, Ene M, Bălănescu E, et al. TH17 and IL-17 immunity in chronic hepatitis C infection. Rom J Intern Med. 2012;50(1):13-8.
36. Stephens GL, Swerdlow B, Benjamin E, Coyle AJ, Humbles A, Kolbeck R, et al. IL-9 is a TH17-derived cytokine that limits pathogenic activity in organ-specific autoimmune disease. Eur J Immunol. 2011;41(4):952-62.
37. Sousa GM, Oliveira IS, Andrade LJ, Sousa-Atta MLB, Paraná R, Atta AM, et al. Serum levels of TH17 associated cytokines in chronic hepatitis C virus infection. Cytokine. 2012;60(1):138-42.
38. Lee HC, Sung SSJ, Krueger PD, Jo YA, Rosen HR, Ziegler SF, et al. Hepatitis C virus promotes t-helper (TH) 17 responses through thymic stromal lymphopoietin production by infected hepatocytes. Cytokine. 2013;63(3):1314-24.
39. Flynn JK, Dore GJ, Matthews G, Hellard M, Yeung B, Rawlinson WD, et al. Impaired hepatitis C virus (HCV)-specific interferon-γ responses in individuals with HIV who acquire HCV infection: correlation with CD4+ T-cell counts. J Infect Dis. 2012;206(10):1568-76.
40. Fan X, Liu W, Li C, Wang Z, Luo L, Tan D, et al. Circulating TH1 and TH2 cytokines in patients with hepatitis C virus infection. Mediators Inflamm. 1998;7(4):295-7.
41. Cui M, Lv Y, Lu J, Zhang W, Duan Y, Huang Y, et al. Decreased frequency of circulating TH9 cells in patients with chronic hepatitis B infection. J Clin Lab Anal. 2018;32(2):e22246.
42. Liu G, Qian L, Xu T, Yu J, Li M, Cui Y, et al. Changes in the TH9 cell population and related cytokines in the peripheral blood of infants with recurrent wheezing. Cent Eur J Immunol. 2020;45(1):60-8.
43. Lu LF, Lind EF, Gondek DC, Bennett KA, Gleeson MW, Pino-Lagos K, et al. Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature. 2006;442(7106):997-1002.
44. Brown PMJ, Neuman MG. Immunopathogenesis of hepatitis C viral infection: TH1/TH2 responses and the role of cytokines. Clin Biochem. 2001;34(3):167-71.
45. Nowak EC, Weaver CT, Turner H, Begum-Haque S, Becher B, Schreiner B, et al. IL-9 as a mediator of TH17-driven inflammatory disease. J Exp Med. 2009;206(8):1653-60.
46. Elyaman W, Bradshaw EM, Uyttenhove C, Dardalhon V, Awasthi A, Imitola J, et al. IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc Natl Acad Sci U S A. 2009;106(31):12885-90.
47. Jost NH, Abel S, Hutzler M, Sparwasser T, Zimmermann A, Roers A, et al. Regulatory T cells and T-cell-derived IL-10 interfere with effective anti-cytomegalovirus immune response. Immunol Cell Biol. 2014;92(10):860-71.
48. Yazdani R, Shapoori S, Rezaeepoor M, Sanaei R, Ganjalikhani-Hakemi M, Azizi G, et al. Features and roles of T helper 9 cells and interleukin 9 in immunological diseases. Allergol Immunopathol (Madr). 2019;47(1):90-104.
49. Anuradha R, Munisankar S, Bhootra Y, Jagannathan J, Dolla C, Kumaran P, et al. IL-10- and TGFβ-mediated TH9 responses in a human helminth infection. PLoS Negl Trop Dis. 2016;10(1):e0004317.
50. Qing K, Weifeng W, Fan Y, Yuluan Y, Yu P, Yanlan H, et al. Distinct different expression of TH17 and TH9 cells in coxsackie virus B3-induced mice viral myocarditis. Virol J. 2011;8(1):1-7.
51. Helanterä I, Loginov R, Koskinen P, Törnroth T, Grönhagen-Riska C, Lautenschlager I, et al. Persistent cytomegalovirus infection is associated with increased expression of TGF-β1, PDGF-AA and ICAM-1 and arterial intimal thickening in kidney allografts. Nephrol Dial Transplant. 2005;20(4):790-6.
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2. Afshari A, Yaghobi R, Karimi M, Azarpira N, Geramizadeh B, Darbouy M, et al. Association between interleukin-21, 23 and 27 expression and protein level with cytomegalovirus infection in liver transplant recipients. Int J Organ Transplant Med. 2020;11(1):27-36.
3. Requião-Moura LR, Matos ACCd, Pacheco-Silva A. Cytomegalovirus infection in renal transplantation: clinical aspects, management and the perspectives. Einstein (Sao Paulo). 2015;13:142-8.
4. Gaballa A, Alagrafi F, Uhlin M, Stikvoort A, et al. Revisiting the role of γδ T cells in Anti-CMV immune response after transplantation. Viruses. 2021;13(6):1031.
5. Helanterä I, Kyllönen L, Lautenschlager I, Salmela K, Koskinen P, et al. Primary CMV infections are common in kidney transplant recipients after 6 months valganciclovir prophylaxis. Am J Transplant. 2010;10(9):2026-32.
6. Soleimanian S, Yaghobi R, Karimi MH, Geramizadeh B, Roozbeh J, Aghdaie MH, et al. Circulating NKG2C+ NK cell expressing CD107a/LAMP-1 subsets at the onset of CMV reactivation in seropositive kidney transplant recipients. Transpl Immunol. 2021;69:101460.
7. Lilleri D, Zelini P, Fornara C, Zavaglio F, Rampino T, Perez L, et al. Human cytomegalovirus (HCMV)‐specific T cell but not neutralizing or IgG binding antibody responses to glycoprotein complexes gB, gHgLgO, and pUL128L correlate with protection against high HCMV viral load reactivation in solid‐organ transplant recipients. J Med Virol. 2018;90(10):1620-8.
8. Giménez E, Blanco-Lobo P, Munoz-Cobo B, Solano C, Amat P, Pérez-Romero P, et al. Role of cytomegalovirus (CMV)-specific polyfunctional CD8+ T-cells and antibodies neutralizing virus epithelial infection in the control of CMV infection in an allogeneic stem-cell transplantation setting. J Gen Virol. 2015;96(9):2822-31.
9. Gabanti E, Bruno F, Lilleri D, Fornara C, Zelini P, Cane I, et al. Human cytomegalovirus (HCMV)-specific CD4+ and CD8+ T cells are both required for prevention of HCMV disease in seropositive solid-organ transplant recipients. PLoS One. 2014;9(8):e106044.
10. Eyerich S, Eyerich K, Pennino D, Carbone T, Nasorri F, Pallotta S, et al. TH22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J Clin Invest. 2009;119(12):3573-85.
11. Mahnke YD, Beddall MH, Roederer M. OMIP-017: human CD4+ helper T-cell subsets including follicular helper cells. Cytometry A. 2013;83(5):439-40.
12. Luckheeram RV, Zhou R, Verma AD, Xia B. CD4+ T cells: differentiation and functions. Clin Dev Immunol. 2012;2012:925135.
13. Meesing A, Razonable RR. Pharmacologic and immunologic management of cytomegalovirus infection after solid organ and hematopoietic stem cell transplantation. Expert Rev Clin Pharmacol. 2018;11(8):773-88.
14. Jorgenson MR, Hillis MI, Saddler CM, Smith JA, Parajuli S, Mandelbrot DA, et al. Prediction of cytomegalovirus infection: a single-center experience utilizing a newly available cell-mediated immunity assay by flow cytometry, a risk factor screening tool, and serologically demonstrated immunity. Transpl Infect Dis. 2020;22(4):e13311.
15. Lim EY, Jackson SE, Wills MR. The CD4+ T cell response to human cytomegalovirus in healthy and immunocompromised people. Front Cell Infect Microbiol. 2020;10:202.
16. Hassanzadeh Y, Yaghobi R, Pakzad P, Geramizadeh B. Risk assessment of human cytomegalovirus infection in solid organ transplantation: insight into CD4+ T cell subsets. Scand J Immunol. 2022;e13212.
17. Sester M, Sester U, Gartner B, Heine G, Girndt M, Mueller-Lantzsch N, et al. Levels of virus-specific CD4 T cells correlate with cytomegalovirus control and predict virus-induced disease after renal transplantation. Transplantation. 2001;71(9):1287-94.
18. Agha Seyed Hosseini M, Mansourabadi AH, Shams A, Razavi N, Daryabor R, Hasanzadeh M, et al. The role of T helper 9 (TH9) against infectious diseases. Int J Epidemiol Res. 2015;2(4):167-73.
19. Heim J, Almanzar G, Schmalzing M, Gernert M, Tony HP, Prelog M, et al. Induction of IL-9 in peripheral lymphocytes of rheumatoid arthritis patients and healthy donors by TH17-inducing cytokine conditions. Front Immunol. 2021;12:1294.
20. Duhen T, Duhen R, Lanzavecchia A, Sallusto F, Campbell DJ. Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector TH cells. Blood. 2012;119(19):4430-40.
21. Afshari A, Yaghobi R, Karimi MH, Darbouy M, Azarpira N, Geramizadeh B, et al. IL-17 mRNA expression and cytomegalovirus infection in liver transplant patients. Exp Clin Transplant. 2015;13(Suppl 1):83-9.
22. Räihä J, Ortiz F, Mannonen L, Loginov R, Lempinen M, Lautenschlager I, et al. The burden of cytomegalovirus infection remains high in high-risk kidney transplant recipients despite six-month valganciclovir prophylaxis. Transpl Infect Dis. 2021;23(4):e13577.
23. Jackson SE, Mason GM, Wills MR. Human cytomegalovirus immunity and immune evasion. Virus Res. 2011;157(2):151-60.
24. Pang N, Xu J, Qu J, Duan X, Yuan H, Chen G, et al. Peripheral blood TH9 cells reconstitution and its relationship with acute graft-versus-host disease after matched-sibling peripheral blood hematopoietic stem cell transplantation. Am J Transl Res. 2017;9(8):3623-34.
25. Chatterjee S, Clark CE, Lugli E, Roederer M, Nutman TB, et al. Filarial infection modulates the immune response to Mycobacterium tuberculosis through expansion of CD4+ IL-4 memory T cells. J Immunol. 2015;194(6):2706-14.
26. Poulin LF, Richard M, Le Moine A, Kiss R, McKenzie AN, Goldman M, et al. Interleukin-9 promotes eosinophilic rejection of mouse heart allografts. Transplantation. 2003;76(3):572-7.
27. Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Stevens S, Flavell RA, et al. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity. 2008;29(6):947-57.
28. Jabeen R, Kaplan MH. The symphony of the ninth: the development and function of TH9 cells. Curr Opin Immunol. 2012;24(3):303-7.
29. Manzardo A, Henkhaus R, Dhillon S, Butler M, et al. Plasma cytokine levels in children with autistic disorder and unrelated siblings. Int J Dev Neurosci. 2012;30(2):121-7.
30. Ali ME, El-Badawy O, Afifi NA, Eldin AS, Hassan EA, Halby HM, et al. Role of T-helper 9 cells in chronic hepatitis C-infected patients. Viruses. 2018;10(7):341.
31. Abdelhamid AE, Abdel Salam SA, Faheem HA, Ahmed OA, Salah MM, Aly HI, et al. Interleukin-9: investigating its possible role in liver cirrhosis progression and in tumour promotion of hepatocellular carcinoma in chronic HCV infected patients, a single centre study. Microb Infect Dis. 2021;2(2):260-70.
32. McNamara PS, Flanagan BF, Baldwin LM, Newland P, Hart CA, Smyth RL, et al. Interleukin 9 production in the lungs of infants with severe respiratory syncytial virus bronchiolitis. Lancet. 2004;363(9414):1031-7.
33. Guzmán-Fulgencio M, Jiménez JL, Berenguer J, Fernández-Rodríguez A, López JC, Cosín J, et al. Plasma IL-6 and IL-9 predict the failure of interferon-α plus ribavirin therapy in HIV/HCV-coinfected patients. J Antimicrob Chemother. 2012;67(5):1238-45.
34. Nowak EC, Noelle RJ. Interleukin-9 as a T helper type 17 cytokine. Immunology. 2010;131(2):169-73.
35. Bălănescu P, Lădaru A, Voiosu T, Nicolau A, Ene M, Bălănescu E, et al. TH17 and IL-17 immunity in chronic hepatitis C infection. Rom J Intern Med. 2012;50(1):13-8.
36. Stephens GL, Swerdlow B, Benjamin E, Coyle AJ, Humbles A, Kolbeck R, et al. IL-9 is a TH17-derived cytokine that limits pathogenic activity in organ-specific autoimmune disease. Eur J Immunol. 2011;41(4):952-62.
37. Sousa GM, Oliveira IS, Andrade LJ, Sousa-Atta MLB, Paraná R, Atta AM, et al. Serum levels of TH17 associated cytokines in chronic hepatitis C virus infection. Cytokine. 2012;60(1):138-42.
38. Lee HC, Sung SSJ, Krueger PD, Jo YA, Rosen HR, Ziegler SF, et al. Hepatitis C virus promotes t-helper (TH) 17 responses through thymic stromal lymphopoietin production by infected hepatocytes. Cytokine. 2013;63(3):1314-24.
39. Flynn JK, Dore GJ, Matthews G, Hellard M, Yeung B, Rawlinson WD, et al. Impaired hepatitis C virus (HCV)-specific interferon-γ responses in individuals with HIV who acquire HCV infection: correlation with CD4+ T-cell counts. J Infect Dis. 2012;206(10):1568-76.
40. Fan X, Liu W, Li C, Wang Z, Luo L, Tan D, et al. Circulating TH1 and TH2 cytokines in patients with hepatitis C virus infection. Mediators Inflamm. 1998;7(4):295-7.
41. Cui M, Lv Y, Lu J, Zhang W, Duan Y, Huang Y, et al. Decreased frequency of circulating TH9 cells in patients with chronic hepatitis B infection. J Clin Lab Anal. 2018;32(2):e22246.
42. Liu G, Qian L, Xu T, Yu J, Li M, Cui Y, et al. Changes in the TH9 cell population and related cytokines in the peripheral blood of infants with recurrent wheezing. Cent Eur J Immunol. 2020;45(1):60-8.
43. Lu LF, Lind EF, Gondek DC, Bennett KA, Gleeson MW, Pino-Lagos K, et al. Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature. 2006;442(7106):997-1002.
44. Brown PMJ, Neuman MG. Immunopathogenesis of hepatitis C viral infection: TH1/TH2 responses and the role of cytokines. Clin Biochem. 2001;34(3):167-71.
45. Nowak EC, Weaver CT, Turner H, Begum-Haque S, Becher B, Schreiner B, et al. IL-9 as a mediator of TH17-driven inflammatory disease. J Exp Med. 2009;206(8):1653-60.
46. Elyaman W, Bradshaw EM, Uyttenhove C, Dardalhon V, Awasthi A, Imitola J, et al. IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc Natl Acad Sci U S A. 2009;106(31):12885-90.
47. Jost NH, Abel S, Hutzler M, Sparwasser T, Zimmermann A, Roers A, et al. Regulatory T cells and T-cell-derived IL-10 interfere with effective anti-cytomegalovirus immune response. Immunol Cell Biol. 2014;92(10):860-71.
48. Yazdani R, Shapoori S, Rezaeepoor M, Sanaei R, Ganjalikhani-Hakemi M, Azizi G, et al. Features and roles of T helper 9 cells and interleukin 9 in immunological diseases. Allergol Immunopathol (Madr). 2019;47(1):90-104.
49. Anuradha R, Munisankar S, Bhootra Y, Jagannathan J, Dolla C, Kumaran P, et al. IL-10- and TGFβ-mediated TH9 responses in a human helminth infection. PLoS Negl Trop Dis. 2016;10(1):e0004317.
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| Cytomegalovirus Interleukin-9 Kidney transplant T-helper9 | ||
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How to Cite
1.
Roostaee A, Yaghobi R, Afshari A, Jafarinia M. Phenotyping of TH9 Cells in Cytomegalovirus-reactivated Kidney Transplant Recipients. Iran J Allergy Asthma Immunol. 2026;:1-17.
