Background CMV-specific T-cells are crucial to control CMV-replication post-transplant. Regulatory T-cells (T-regs) are associated with a tolerant immune state and may contribute to CMV-replication. However, T-cell subsets such as T-regs and IL-17 producing T-cells (Th-17) are not well studied in this context. We explored T-regs and Th-17 frequencies during CMV-replication after transplantation. Methods We prospectively evaluated 30 transplant patients with CMV-viremia. We quantified CMV-specific CD4+ and CD8+ T-cells, T-regs (CD4+CD25+FoxP3+) and Th-17 frequencies using flow-cytometry and followed patients requiring anti-viral treatment. Two subsets were compared: anti-viral treatment requirement (n = 20) vs. spontaneous clearance of viremia (n = 10). Results Higher initial CMV-specific CD4+ T-cells and lower T-regs were observed in patients with spontaneous clearance (p = 0.043; p = 0.021 respectively). Using a ratio of CMV-specific CD4+ T-cells to T-regs allowed prediction of viral clearance with 80% sensitivity and 90% specificity (p = 0.001). One month after stop of treatment, the same correlation was observed in patients protected from CMV-relapse. The ratio of CMV-specific CD4+ T-cells to T-regs allowed prediction of relapse with 85% sensitivity and 86% specificity (p = 0.004). Th-17 responses were not correlated with virologic outcomes. Conclusions This study provides novel insights into T-regs and Th-17 subpopulations during CMV-replication after transplantation. These preliminary data suggest that measurement of CMV-specific CD4+ T-cells together with T-regs has value in predicting spontaneous clearance of viremia and relapse.
References
[1]
Humar A, Snydman D (2009) Cytomegalovirus in solid organ transplant recipients. Am J Transplant 9 Suppl 4: S78–86.
[2]
Freeman RB Jr (2009) The ‘indirect’ effects of cytomegalovirus infection. Am J Transplant 9: 2453–2458.
[3]
Bunde T, Kirchner A, Hoffmeister B, Habedank D, Hetzer R, et al. (2005) Protection from cytomegalovirus after transplantation is correlated with immediate early 1-specific CD8 T cells. J Exp Med 201: 1031–1036.
[4]
Egli A, Binet I, Binggeli S, Jager C, Dumoulin A, et al. (2008) Cytomegalovirus-specific T-cell responses and viral replication in kidney transplant recipients. J Transl Med 6: 29.
[5]
Gerna G, Lilleri D, Fornara C, Comolli G, Lozza L, et al. (2006) Monitoring of human cytomegalovirus-specific CD4 and CD8 T-cell immunity in patients receiving solid organ transplantation. Am J Transplant 6: 2356–2364.
[6]
Kumar D, Chernenko S, Moussa G, Cobos I, Manuel O, et al. (2009) Cell-mediated immunity to predict cytomegalovirus disease in high-risk solid organ transplant recipients. Am J Transplant 9: 1214–1222.
[7]
Lilleri D, Zelini P, Fornara C, Comolli G, Gerna G (2007) Inconsistent responses of cytomegalovirus-specific T cells to pp65 and IE-1 versus infected dendritic cells in organ transplant recipients. Am J Transplant 7: 1997–2005.
[8]
Sester M, Sester U, Gartner B, Heine G, Girndt M, et al. (2001) Levels of virus-specific CD4 T cells correlate with cytomegalovirus control and predict virus-induced disease after renal transplantation. Transplantation 71: 1287–1294.
[9]
Swain SL, McKinstry KK, Strutt TM (2012) Expanding roles for CD4+ T cells in immunity to viruses. Nature Reviews Immunology doi:10.1038/nri3152.
[10]
Boros P, Bromberg JS (2009) Human FOXP3+ regulatory T cells in transplantation. Am J Transplant 9: 1719–1724.
[11]
Louis S, Braudeau C, Giral M, Dupont A, Moizant F, et al. (2006) Contrasting CD25hiCD4+T cells/FOXP3 patterns in chronic rejection and operational drug-free tolerance. Transplantation 81: 398–407.
[12]
Carpentier A, Conti F, Stenard F, Aoudjehane L, Miroux C, et al. (2009) Increased expression of regulatory Tr1 cells in recurrent hepatitis C after liver transplantation. Am J Transplant 9: 2102–2112.
[13]
Heidt S, Segundo DS, Chadha R, Wood KJ (2010) The impact of Th17 cells on transplant rejection and the induction of tolerance. Curr Opin Organ Transplant 15: 456–461.
[14]
Mitchell P, Afzali B, Lombardi G, Lechler RI (2009) The T helper 17-regulatory T cell axis in transplant rejection and tolerance. Curr Opin Organ Transplant 14: 326–331.
[15]
Arens R, Wang P, Sidney J, Loewendorf A, Sette A, et al. (2008) Cutting edge: murine cytomegalovirus induces a polyfunctional CD4 T cell response. J Immunol 180: 6472–6476.
[16]
Suryawanshi A, Veiga-Parga T, Rajasagi NK, Reddy PB, Sehrawat S, et al. (2011) Role of IL-17 and Th17 cells in herpes simplex virus-induced corneal immunopathology. J Immunol 187: 1919–1930.
[17]
McKinstry KK, Strutt TM, Buck A, Curtis JD, Dibble JP, et al. (2009) IL-10 deficiency unleashes an influenza-specific Th17 response and enhances survival against high-dose challenge. J Immunol 182: 7353–7363.
[18]
Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, et al. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation 89: 779–795.
[19]
Pang XL, Chui L, Fenton J, LeBlanc B, Preiksaitis JK (2003) Comparison of LightCycler-based PCR, COBAS amplicor CMV monitor, and pp65 antigenemia assays for quantitative measurement of cytomegalovirus viral load in peripheral blood specimens from patients after solid organ transplantation. J Clin Microbiol 41: 3167–3174.
[20]
Lisboa LF, Asberg A, Kumar D, Pang X, Hartmann A, et al. (2011) The clinical utility of whole blood versus plasma cytomegalovirus viral load assays for monitoring therapeutic response. Transplantation 91: 231–236.
[21]
Humar A, Kumar D, Boivin G, Caliendo AM (2002) Cytomegalovirus (CMV) virus load kinetics to predict recurrent disease in solid-organ transplant patients with CMV disease. J Infect Dis 186: 829–833.
[22]
Sester U, Gartner BC, Wilkens H, Schwaab B, Wossner R, et al. (2005) Differences in CMV-specific T-cell levels and long-term susceptibility to CMV infection after kidney, heart and lung transplantation. Am J Transplant 5: 1483–1489.
[23]
Wu C, Wang S, Wang F, Chen Q, Peng S, et al. (2009) Increased frequencies of T helper type 17 cells in the peripheral blood of patients with acute myeloid leukaemia. Clin Exp Immunol 158: 199–204.
[24]
Eid AJ, Brown RA, Arthurs SK, Lahr BD, Eckel-Passow JE, et al. A prospective longitudinal analysis of cytomegalovirus (CMV)-specific CD4+ and CD8+ T cells in kidney allograft recipients at risk of CMV infection. Transpl Int 23: 506–513.
[25]
Pastore D, Delia M, Mestice A, Perrone T, Carluccio P, et al. Recovery of CMV-specific CD8(+) T cells and T regs after allogeneic peripheral blood stem cell transplantation. Biol Blood Marrow Transplant
[26]
La Rosa C, Limaye AP, Krishnan A, Longmate J, Diamond DJ (2007) Longitudinal assessment of cytomegalovirus (CMV)-specific immune responses in liver transplant recipients at high risk for late CMV disease. J Infect Dis 195: 633–644.
[27]
Rouse BT, Sarangi PP, Suvas S (2006) Regulatory T cells in virus infections. Immunol Rev 212: 272–286.
[28]
Rouse BT, Sehrawat S (2010) Immunity and immunopathology to viruses: what decides the outcome? Nat Rev Immunol 10: 514–526.
[29]
Zhao J, Fett C, Trandem K, Fleming E, Perlman S (2011) IFN-gamma- and IL-10-expressing virus epitope-specific Foxp3(+) T reg cells in the central nervous system during encephalomyelitis. J Exp Med 208: 1571–1577.
[30]
Lanteri MC, O'Brien KM, Purtha WE, Cameron MJ, Lund JM, et al. (2009) Tregs control the development of symptomatic West Nile virus infection in humans and mice. J Clin Invest 119: 3266–3277.
[31]
Lee DC, Harker JA, Tregoning JS, Atabani SF, Johansson C, et al. (2010) CD25+ natural regulatory T cells are critical in limiting innate and adaptive immunity and resolving disease following respiratory syncytial virus infection. J Virol 84: 8790–8798.
[32]
Antunes I, Kassiotis G (2010) Suppression of innate immune pathology by regulatory T cells during Influenza A virus infection of immunodeficient mice. J Virol 84: 12564–12575.
[33]
Robertson SJ, Hasenkrug KJ (2006) The role of virus-induced regulatory T cells in immunopathology. Springer Semin Immunopathol 28: 51–62.
[34]
Punkosdy GA, Blain M, Glass DD, Lozano MM, O'Mara L, et al. (2011) Regulatory T-cell expansion during chronic viral infection is dependent on endogenous retroviral superantigens. Proc Natl Acad Sci U S A 108: 3677–3682.
[35]
Suvas S, Azkur AK, Kim BS, Kumaraguru U, Rouse BT (2004) CD4+CD25+ regulatory T cells control the severity of viral immunoinflammatory lesions. J Immunol 172: 4123–4132.
[36]
Haeryfar SM, DiPaolo RJ, Tscharke DC, Bennink JR, Yewdell JW (2005) Regulatory T cells suppress CD8+ T cell responses induced by direct priming and cross-priming and moderate immunodominance disparities. J Immunol 174: 3344–3351.
[37]
Presser D, Sester U, Mohrbach J, Janssen M, Kohler H, et al. (2009) Differential kinetics of effector and regulatory T cells in patients on calcineurin inhibitor-based drug regimens. Kidney Int 76: 557–566.
[38]
Curotto de Lafaille MA, Lafaille JJ (2009) Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Immunity 30: 626–635.
[39]
Amarnath S, Dong L, Li J, Wu Y, Chen W (2007) Endogenous TGF-beta activation by reactive oxygen species is key to Foxp3 induction in TCR-stimulated and HIV-1-infected human CD4+CD25？ T cells. Retrovirology 4: 57.
[40]
Tovar-Salazar A, Patterson-Bartlett J, Jesser R, Weinberg A (2010) Regulatory function of cytomegalovirus-specific CD4+CD27？CD28？ T cells. Virology 398: 158–167.
[41]
Hou W, Kang HS, Kim BS (2009) Th17 cells enhance viral persistence and inhibit T cell cytotoxicity in a model of chronic virus infection. J Exp Med 206: 313–328.
[42]
Asberg A, Humar A, Rollag H, Jardine AG, Mouas H, et al. (2007) Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant 7: 2106–2113.
[43]
Asberg A, Jardine AG, Bignamini AA, Rollag H, Pescovitz MD, et al. (2010) Effects of the intensity of immunosuppressive therapy on outcome of treatment for CMV disease in organ transplant recipients. Am J Transplant 10: 1881–1888.
