Natural regulatory T cells inhibit production of cytotoxic molecules in CD8+T cells during low-level Friend retrovirus infection
© Zelinskyy et al.; licensee BioMed Central Ltd. 2013
Received: 5 June 2013
Accepted: 10 October 2013
Published: 24 October 2013
Cytotoxic T cells (CTL) play a central role in the control of viral infections. Their antiviral activity can be mediated by at least two cytotoxic pathways, namely the granule exocytosis pathway, involving perforin and granzymes, and the Fas-FasL pathway. It was shown that the level of Friend retrovirus (FV) replication determines the cytotoxic pathway for the control of viral infection. In low-level infection only the Fas pathway is active, whereas cytotoxic molecules are not produced. In the current study, we elucidate the role of CD4+ regulatory T cells (Tregs) in suppressing the exocytosis pathway during an asymptomatic low-level infection.
We show that even a low-level retrovirus infection induced a strong activation and proliferation of natural Tregs. The expanded Tregs suppressed the proliferation of virus-specific CD8+ T cells and the production of cytotoxic molecules by these cells. Not surprisingly, the in vivo killing activity of these CD8+ T cells was rather weak. Selective depletion of Foxp3+ Tregs resulted in de novo granzyme production and augmented virus-specific in vivo killing, but did not affect the low-level virus replication.
Expanded natural Tregs determined the cytotoxic pathways of virus-specific effector CD8+ T cells during the acute phase of retroviral infection.
CD8+ cytotoxic T cells (CTL) can eliminate target cells by at least two independent cytolytic pathways, the granule exocytosis pathway and the Fas-FasL pathway . Previously, we compared the CTL response against low-and high-level Friend retrovirus (FV) infection of mice . Low-level infection induced moderate activation of CD8+ T cells expressing only FasL, whereas high-level infection resulted in extensive expansion of CD8+ effector T cells secreting molecules of the exocytosis pathway. In an in vitro model of HBV infection  it was also described that virus antigen levels were critical for regulating the quality of antigen-specific CD8+ T cells. It was concluded that stronger antigen stimulation is needed for the production of granzymes compared to FasL . Along these lines, a certain density of antigen presented on DC was necessary for the differentiation of cytotoxic CD8+ T cells . These publications acknowledge the significance of antigen levels for CD8+ T cell cytotoxicity, whereas the mechanisms that suppress the production of cytotoxic molecules in low-level virus infections were unknown. In addition, most of our basic concepts on the regulation of acute anti-viral immune responses are derived from model infections with high viral loads (e.g. LCMV), whereas the immune responses to low-level asymptomatic infections are poorly defined. A more detailed understanding of such infection courses is very important especially in chronic viral infections as acute viral loads have been shown to correlate significantly with chronic viral set points and onset of chronic disease in infections like HCV or HIV [6, 7]. In HCV infected patients, an acute low-level asymptomatic infection even results significantly more often in chronicity and thus is a negative prognostic factor .
The work was supported by the DFG Transregio 60, project B4.
We thank Tim Sparwasser (Institute for Infection Immunology, TWINCORE, Hannover, Germany) for providing DEREG mice, and Markus Simon (Max-Plank-Institut für Immunbiology, Freiburg, Germany) for providing the anti-granzyme A antibodies. We thank the NIH tetramer facility for providing MHC class II tetramers.
- Russell JH, Ley TJ: Lymphocyte-mediated cytotoxicity. Annu Rev Immunol. 2002, 20: 323-370. 10.1146/annurev.immunol.20.100201.131730.View ArticlePubMedGoogle Scholar
- Zelinskyy G, Balkow S, Schimmer S, Werner T, Simon MM, Dittmer U: The level of friend retrovirus replication determines the cytolytic pathway of CD8+ T-cell-mediated pathogen control. J Virol. 2007, 81: 11881-11890. 10.1128/JVI.01554-07.PubMed CentralView ArticlePubMedGoogle Scholar
- Gehring AJ, Sun D, Kennedy PT, Nolte-'t Hoen E, Lim SG, Wasser S, Selden C, Maini MK, Davis DM, Nassal M, Bertoletti A: The level of viral antigen presented by hepatocytes influences CD8 T-cell function. J Virol. 2007, 81: 2940-2949. 10.1128/JVI.02415-06.PubMed CentralView ArticlePubMedGoogle Scholar
- He JS, Gong DE, Ostergaard HL: Stored Fas ligand, a mediator of rapid CTL-mediated killing, has a lower threshold for response than degranulation or newly synthesized Fas ligand. J Immunol. 2010, 184: 555-563. 10.4049/jimmunol.0902465.View ArticlePubMedGoogle Scholar
- Henrickson SE, Mempel TR, Mazo IB, Liu B, Artyomov MN, Zheng H, Peixoto A, Flynn MP, Senman B, Junt T, et al: T cell sensing of antigen dose governs interactive behavior with dendritic cells and sets a threshold for T cell activation. Nat Immunol. 2008, 9: 282-291. 10.1038/ni1559.PubMed CentralView ArticlePubMedGoogle Scholar
- Cohen MS, Shaw GM, McMichael AJ, Haynes BF: Acute HIV-1 Infection. New England J Med. 2011, 364: 1943-1954. 10.1056/NEJMra1011874.View ArticleGoogle Scholar
- Maheshwari A, Ray S, Thuluvath PJ: Acute hepatitis C. Lancet. 2008, 372: 321-332. 10.1016/S0140-6736(08)61116-2.View ArticlePubMedGoogle Scholar
- Zelinskyy G, Kraft AR, Schimmer S, Arndt T, Dittmer U: Kinetics of CD8+ effector T cell responses and induced CD4+ regulatory T cell responses during Friend retrovirus infection. Eur J Immunol. 2006, 36: 2658-2670. 10.1002/eji.200636059.View ArticlePubMedGoogle Scholar
- Zelinskyy G, Dietze KK, Husecken YP, Schimmer S, Nair S, Werner T, Gibbert K, Kershaw O, Gruber AD, Sparwasser T, Dittmer U: The regulatory T-cell response during acute retroviral infection is locally defined and controls the magnitude and duration of the virus-specific cytotoxic T-cell response. Blood. 2009, 114: 3199-3207. 10.1182/blood-2009-03-208736.View ArticlePubMedGoogle Scholar
- Zelinskyy G, Dietze K, Sparwasser T, Dittmer U: Regulatory T cells suppress antiviral immune responses and increase viral loads during acute infection with a lymphotropic retrovirus. PLoS Pathog. 2009, 5: e1000406-10.1371/journal.ppat.1000406.PubMed CentralView ArticlePubMedGoogle Scholar
- Dietze KK, Zelinskyy G, Gibbert K, Schimmer S, Francois S, Myers L, Sparwasser T, Hasenkrug KJ, Dittmer U: Transient depletion of regulatory T cells in transgenic mice reactivates virus-specific CD8+ T cells and reduces chronic retroviral set points. Proc Natl Acad Sci U S A. 2011, 108: 2420-2425. 10.1073/pnas.1015148108.PubMed CentralView ArticlePubMedGoogle Scholar
- Estes JD, Li Q, Reynolds MR, Wietgrefe S, Duan L, Schacker T, Picker LJ, Watkins DI, Lifson JD, Reilly C, et al: Premature induction of an immunosuppressive regulatory T cell response during acute simian immunodeficiency virus infection. J Infect Dis. 2006, 193: 703-712. 10.1086/500368.View ArticlePubMedGoogle Scholar
- Lanteri MC, O'Brien KM, Purtha WE, Cameron MJ, Lund JM, Owen RE, Heitman JW, Custer B, Hirschkorn DF, Tobler LH, et al: Tregs control the development of symptomatic West Nile virus infection in humans and mice. J Clin Invest. 2009, 119: 3266-3277.PubMed CentralPubMedGoogle Scholar
- Mexas AM, Fogle JE, Tompkins WA, Tompkins MB: CD4 + CD25+ regulatory T cells are infected and activated during acute FIV infection. Vet Immunol Immunopathol. 2008, 126: 263-272. 10.1016/j.vetimm.2008.08.003.PubMed CentralView ArticlePubMedGoogle Scholar
- Ndhlovu LC, Loo CP, Spotts G, Nixon DF, Hecht FM: FOXP3 expressing CD127lo CD4+ T cells inversely correlate with CD38+ CD8+ T cell activation levels in primary HIV-1 infection. J Leukoc Biol. 2008, 83: 254-262.View ArticlePubMedGoogle Scholar
- Schepers K, Toebes M, Sotthewes G, Vyth-Dreese FA, Dellemijn TA, Melief CJ, Ossendorp F, Schumacher TN: Differential kinetics of antigen-specific CD4+ and CD8+ T cell responses in the regression of retrovirus-induced sarcomas. J Immunol. 2002, 169: 3191-3199.View ArticlePubMedGoogle Scholar
- Schluter C, Duchrow M, Wohlenberg C, Becker MH, Key G, Flad HD, Gerdes J: The cell proliferation-associated antigen of antibody Ki-67: a very large, ubiquitous nuclear protein with numerous repeated elements, representing a new kind of cell cycle-maintaining proteins. J Cell Biol. 1993, 123: 513-522. 10.1083/jcb.123.3.513.View ArticlePubMedGoogle Scholar
- Curotto de Lafaille MA, Lafaille JJ: Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor?. Immunity. 2009, 30: 626-635. 10.1016/j.immuni.2009.05.002.View ArticlePubMedGoogle Scholar
- Weiss JM, Bilate AM, Gobert M, Ding Y, Curotto de Lafaille MA, Parkhurst CN, Xiong H, Dolpady J, Frey AB, Ruocco MG, et al: Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J Experimental Med. 2012, 209: 1723-1742. 10.1084/jem.20120914. S1721View ArticleGoogle Scholar
- Yadav M, Louvet C, Davini D, Gardner JM, Martinez-Llordella M, Bailey-Bucktrout S, Anthony BA, Sverdrup FM, Head R, Kuster DJ, et al: Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Experimental Med. 2012, 209: 1713-1722. 10.1084/jem.20120822. S1711-1719View ArticleGoogle Scholar
- Akimova T, Beier UH, Wang L, Levine MH, Hancock WW: Helios expression is a marker of T cell activation and proliferation. PloS one. 2011, 6: e24226-10.1371/journal.pone.0024226.PubMed CentralView ArticlePubMedGoogle Scholar
- Zabransky DJ, Nirschl CJ, Durham NM, Park BV, Ceccato CM, Bruno TC, Tam AJ, Getnet D, Drake CG: Phenotypic and functional properties of Helios + regulatory T cells. PloS one. 2012, 7: e34547-10.1371/journal.pone.0034547.PubMed CentralView ArticlePubMedGoogle Scholar
- Lahl K, Loddenkemper C, Drouin C, Freyer J, Arnason J, Eberl G, Hamann A, Wagner H, Huehn J, Sparwasser T: Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J Exp Med. 2007, 204: 57-63. 10.1084/jem.20061852.PubMed CentralView ArticlePubMedGoogle Scholar
- Kim J, Lahl K, Hori S, Loddenkemper C, Chaudhry A, DeRoos P, Rudensky A, Sparwasser T: Cutting edge: depletion of Foxp3+ cells leads to induction of autoimmunity by specific ablation of regulatory T cells in genetically targeted mice. J Immunol. 2009, 183: 7631-7634. 10.4049/jimmunol.0804308.View ArticlePubMedGoogle Scholar
- Pearce EL, Mullen AC, Martins GA, Krawczyk CM, Hutchins AS, Zediak VP, Banica M, DiCioccio CB, Gross DA, Mao CA, et al: Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science. 2003, 302: 1041-1043. 10.1126/science.1090148.View ArticlePubMedGoogle Scholar
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