The Experts below are selected from a list of 9234 Experts worldwide ranked by ideXlab platform
Ulf Dittmer - One of the best experts on this subject based on the ideXlab platform.
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granulocytic myeloid derived suppressor cells suppress virus specific cd8 t cell responses during acute friend Retrovirus Infection
Retrovirology, 2017Co-Authors: Malgorzata Drabczykpluta, Ulf Dittmer, Tanja Werner, Daniel Hoffmann, Qibin Leng, Lieping Chen, Gennadiy ZelinskyyAbstract:Myeloid-derived suppressor cells (MDSCs) can suppress T cell responses in several different diseases. Previously these suppressive cells were observed to expand in HIV patients and in a mouse Retrovirus model, yet their suppressive effect on virus-specific CD8+ T cells in vitro and in vivo has not been characterized thus far. We used the Friend Retrovirus (FV) model to demonstrate that MDSCs expand and become activated during the late phase of acute FV Infection. Only the subpopulation of granulocytic MDSCs (gMDSCs) but not monocytic MDSC suppressed virus-specific CD8+ T cell proliferation and function in vitro. gMDSCs expressed arginase 1, high levels of the inhibitory ligand PD-L1 and the ATP dephosphorylating enzyme CD39 on the cell surface upon Infection. All three molecules were involved in the suppressive effect of the gMDSCs in vitro. MDSC depletion experiments in FV-infected mice revealed that they restrict virus-specific CD8+ T cell responses and thus affect the immune control of chronic Retroviruses in vivo. Our study demonstrates that MDSCs become activated and expand during the acute phase of Retrovirus Infection. Their suppressive activity on virus-specific CD8+ T cells may contribute to T cell dysfunction and the development of chronic Infection.
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fas ligand mediated cytotoxicity of cd4 t cells during chronic Retrovirus Infection
Scientific Reports, 2017Co-Authors: A I Malyshkina, Kim J. Hasenkrug, Gennadiy Zelinskyy, Simone Schimmer, Elisabeth Littwitzsalomon, Kathrin Sutter, Sonja Windmann, Annette Paschen, Hendrik Streeck, Ulf DittmerAbstract:CD4+ helper T cells and cytotoxic CD8+ T cells are key players for adaptive immune responses against acute Infections with Retroviruses. Similar to textbook knowledge the most important function of CD4+ T cells during an acute Retrovirus Infection seems to be their helper function for other immune cells. Whereas there was no direct anti-viral activity of CD4+ T cells during acute Friend Virus (FV) Infection, they were absolutely required for the control of chronic Infection. During chronic FV Infection a population of activated FV-specific CD4+ T cells did not express cytotoxic molecules, but Fas Ligand that can induce Fas-induced apoptosis in target cells. Using an MHC II-restricted in vivo CTL assay we demonstrated that FV-specific CD4+ T cells indeed mediated cytotoxic effects against FV epitope peptide loaded targets. CD4 + CTL killing was also detected in FV-infected granzyme B knockout mice confirming that the exocytosis pathway was not involved. However, killing could be blocked by antibodies against FasL, which identified the Fas/FasL pathway as critical cytotoxic mechanism during chronic FV Infection. Interestingly, targeting the co-stimulatory receptor CD137 with an agonistic antibody enhanced CD4+ T cell cytotoxicity. This immunotherapy may be an interesting new approach for the treatment of chronic viral Infections.
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tetherin bst 2 promotes dendritic cell activation and function during acute Retrovirus Infection
Scientific Reports, 2016Co-Authors: Bradley S Barrett, Kim J. Hasenkrug, Kejun Guo, George Kassiotis, Ulf Dittmer, Kathrin Gibbert, Mario L SantiagoAbstract:Tetherin/BST-2 is a host restriction factor that inhibits Retrovirus release from infected cells in vitro by tethering nascent virions to the plasma membrane. However, contradictory data exists on whether Tetherin inhibits acute Retrovirus Infection in vivo. Previously, we reported that Tetherin-mediated inhibition of Friend Retrovirus (FV) replication at 2 weeks post-Infection correlated with stronger natural killer, CD4+ T and CD8+ T cell responses. Here, we further investigated the role of Tetherin in counteracting Retrovirus replication in vivo. FV Infection levels were similar between wild-type (WT) and Tetherin KO mice at 3 to 7 days post-Infection despite removal of a potent restriction factor, Apobec3/Rfv3. However, during this phase of acute Infection, Tetherin enhanced myeloid dendritic cell (DC) function. DCs from infected, but not uninfected, WT mice expressed significantly higher MHC class II and the co-stimulatory molecule CD80 compared to Tetherin KO DCs. Tetherin-associated DC activation during acute FV Infection correlated with stronger NK cell responses. Furthermore, Tetherin+ DCs from FV-infected mice more strongly stimulated FV-specific CD4+ T cells ex vivo compared to Tetherin KO DCs. The results link the antiretroviral and immunomodulatory activity of Tetherin in vivo to improved DC activation and MHC class II antigen presentation.
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tlr ligand induced il 6 counter regulates the anti viral cd8 t cell response during an acute Retrovirus Infection
Scientific Reports, 2015Co-Authors: Kirsten K Dietze, Ulf Dittmer, Kathrin Gibbert, Michael Roggendorf, Karl S Lang, Mirko Trilling, Huimin Yan, Dongliang Yang, Jia LiuAbstract:We have previously shown that Toll-like receptor (TLR) agonists contribute to the control of viral Infection by augmenting virus-specific CD8+ T-cell responses. It is also well established that signaling by TLRs results in the production of pro-inflammatory cytokines such as interleukin 6 (IL-6). However, how these pro-inflammatory cytokines influence the virus-specific CD8+ T-cell response during the TLR agonist stimulation remained largely unknown. Here, we investigated the role of TLR-induced IL-6 in shaping virus-specific CD8+ T-cell responses in the Friend Retrovirus (FV) mouse model. We show that the TLR agonist induced IL-6 counter-regulates effector CD8+ T-cell responses. IL-6 potently inhibited activation and cytokine production of CD8+ T cells in vitro. This effect was mediated by a direct stimulation of CD8+ T cells by IL-6, which induced upregulation of STAT3 phosphorylation and SOCS3 and downregulated STAT4 phosphorylation and T-bet. Moreover, combining TLR stimulation and IL-6 blockade during an acute FV Infection resulted in enhanced virus-specific CD8+ T-cell immunity and better control of viral replication. These results have implications for our understanding of the role of TLR induced pro-inflammatory cytokines in regulating effector T cell responses and for the development of therapeutic strategies to overcome T cell dysfunction in chronic viral Infections.
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the phenotype and activation status of regulatory t cells during friend Retrovirus Infection
Virologica Sinica, 2014Co-Authors: Jara J Joedicke, Kirsten K Dietze, Gennadiy Zelinskyy, Ulf DittmerAbstract:The suppressive capacity of regulatory T cells (Tregs) has been extensively studied and is well established for many diseases. The expansion, accumulation, and activation of Tregs in viral Infections are of major interest in order to find ways to alter Treg functions for therapeutic benefit. Tregs are able to dampen effector T cell responses to viral Infections and thereby contribute to the establishment of a chronic Infection. In the Friend Retrovirus (FV) mouse model, Tregs are known to expand in all infected organs. To better understand the characteristics of these Treg populations, their phenotype was analyzed in detail. During acute FV-Infection, Tregs became activated in the spleen and bone marrow, as indicated by various T cell activation markers, such as CD43 and CD103. Interestingly, Tregs in the bone marrow, which contains the highest viral loads during acute Infection, displayed greater levels of activation than Tregs from the spleen. Treg expansion was driven by proliferation but no FV-specific Tregs could be detected. Activated Tregs in FV-Infection did not produce Granzyme B (GzmB) or tumor necrosis factor α (TNFα), which are thought to be a potential mechanism for their suppressive activity. Furthermore, Tregs expressed inhibitory markers, such as TIM3, PD-1 and PD-L1. Blocking TIM3 and PD-L1 with antibodies during chronic FV-Infection increased the numbers of activated Tregs. These data may have important implications for the understanding of Treg functions during chronic viral Infections.
Kim J. Hasenkrug - One of the best experts on this subject based on the ideXlab platform.
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fas ligand mediated cytotoxicity of cd4 t cells during chronic Retrovirus Infection
Scientific Reports, 2017Co-Authors: A I Malyshkina, Kim J. Hasenkrug, Gennadiy Zelinskyy, Simone Schimmer, Elisabeth Littwitzsalomon, Kathrin Sutter, Sonja Windmann, Annette Paschen, Hendrik Streeck, Ulf DittmerAbstract:CD4+ helper T cells and cytotoxic CD8+ T cells are key players for adaptive immune responses against acute Infections with Retroviruses. Similar to textbook knowledge the most important function of CD4+ T cells during an acute Retrovirus Infection seems to be their helper function for other immune cells. Whereas there was no direct anti-viral activity of CD4+ T cells during acute Friend Virus (FV) Infection, they were absolutely required for the control of chronic Infection. During chronic FV Infection a population of activated FV-specific CD4+ T cells did not express cytotoxic molecules, but Fas Ligand that can induce Fas-induced apoptosis in target cells. Using an MHC II-restricted in vivo CTL assay we demonstrated that FV-specific CD4+ T cells indeed mediated cytotoxic effects against FV epitope peptide loaded targets. CD4 + CTL killing was also detected in FV-infected granzyme B knockout mice confirming that the exocytosis pathway was not involved. However, killing could be blocked by antibodies against FasL, which identified the Fas/FasL pathway as critical cytotoxic mechanism during chronic FV Infection. Interestingly, targeting the co-stimulatory receptor CD137 with an agonistic antibody enhanced CD4+ T cell cytotoxicity. This immunotherapy may be an interesting new approach for the treatment of chronic viral Infections.
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b cell requirement for robust regulatory t cell responses to friend Retrovirus Infection
Mbio, 2017Co-Authors: Tyler C Moore, Ronald J Messer, Lorena M Gonzaga, Jennifer M Mather, Kim J. HasenkrugAbstract:Regulatory T cells (Tregs) are immunosuppressive cells of the immune system that control autoimmune reactivity. Tregs also respond during immune reactions to infectious agents in order to limit immunopathological damage from potent effectors such as CD8+ cytolytic T lymphocytes. We have used the Friend virus (FV) model of retroviral Infection in mice to investigate how viral Infections induce Tregs. During acute FV Infection, there is significant activation and expansion of thymus-derived (natural) Tregs that suppress virus-specific CD8+ T cell responses. Unlike conventional T cells, the responding Tregs are not virus specific, so the mechanisms that induce their expansion are of great interest. We now show that B cells provide essential signals for Treg expansion during FV Infection. Treg responses are greatly diminished in B cell-deficient mice but can be restored by adoptive transfers of B cells at the time of Infection. The feeble Treg responses in B cell-deficient mice are associated with enhanced virus-specific CD8+ T cell responses and accelerated virus control during the first 2 weeks of Infection. In vitro experiments demonstrated that B cells promote Treg activation and proliferation through a glucocorticoid-induced receptor superfamily member 18 (GITR) ligand-dependent mechanism. Thus, B cells play paradoxically opposing roles during FV Infection. They provide proliferative signals to immunsosuppressive Tregs, which slows early virus control, and they also produce virus-specific antibodies, which are essential for long-term virus control.IMPORTANCE When infectious agents invade a host, numerous immunological mechanisms are deployed to limit their replication, neutralize their spread, and destroy the host cells harboring the Infection. Since immune responses also have a strong capacity to damage host cells and tissues, their magnitude, potency, and duration are under regulatory control. Regulatory T cells are an important component of this control, and the mechanisms that induce them to respond and exert immunosuppressive regulation are of great interest. In the current report, we show that B cells, the cells responsible for making pathogen-specific antibodies, are also involved in promoting the expansion of regulatory T cells during a retroviral Infection. In vitro studies demonstrated that they do so via stimulation of the Tregs through interactions between cell surface molecules: GITR interactions with its ligand (GITRL) on B cells and GITR on regulatory T cells. These findings point the way toward therapeutics to better treat Infections and autoimmune diseases.
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tetherin bst 2 promotes dendritic cell activation and function during acute Retrovirus Infection
Scientific Reports, 2016Co-Authors: Bradley S Barrett, Kim J. Hasenkrug, Kejun Guo, George Kassiotis, Ulf Dittmer, Kathrin Gibbert, Mario L SantiagoAbstract:Tetherin/BST-2 is a host restriction factor that inhibits Retrovirus release from infected cells in vitro by tethering nascent virions to the plasma membrane. However, contradictory data exists on whether Tetherin inhibits acute Retrovirus Infection in vivo. Previously, we reported that Tetherin-mediated inhibition of Friend Retrovirus (FV) replication at 2 weeks post-Infection correlated with stronger natural killer, CD4+ T and CD8+ T cell responses. Here, we further investigated the role of Tetherin in counteracting Retrovirus replication in vivo. FV Infection levels were similar between wild-type (WT) and Tetherin KO mice at 3 to 7 days post-Infection despite removal of a potent restriction factor, Apobec3/Rfv3. However, during this phase of acute Infection, Tetherin enhanced myeloid dendritic cell (DC) function. DCs from infected, but not uninfected, WT mice expressed significantly higher MHC class II and the co-stimulatory molecule CD80 compared to Tetherin KO DCs. Tetherin-associated DC activation during acute FV Infection correlated with stronger NK cell responses. Furthermore, Tetherin+ DCs from FV-infected mice more strongly stimulated FV-specific CD4+ T cells ex vivo compared to Tetherin KO DCs. The results link the antiretroviral and immunomodulatory activity of Tetherin in vivo to improved DC activation and MHC class II antigen presentation.
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tetherin promotes the innate and adaptive cell mediated immune response against Retrovirus Infection in vivo
Journal of Immunology, 2014Co-Authors: Bradley S Barrett, Karl J Heilman, Kim J. Hasenkrug, Ronald J Messer, Rachel A. Liberatore, George Kassiotis, Mario L SantiagoAbstract:Tetherin/BST-2 is a host restriction factor that could directly inhibit retroviral particle release by tethering nascent virions to the plasma membrane. However, the immunological impact of Tetherin during Retrovirus Infection remains unknown. We now show that Tetherin influences antiretroviral cell-mediated immune responses. In contrast to the direct antiviral effects of Tetherin, which are dependent on cell surface expression, the immunomodulatory effects are linked to the endocytosis of the molecule. Mice encoding endocytosis-competent C57BL/6 Tetherin exhibited lower viremia and pathology at 7 d postInfection with Friend Retrovirus (FV) compared with mice encoding endocytosis-defective NZW/LacJ Tetherin. Notably, antiretroviral protection correlated with stronger NK cell responses. In addition, Friend Retrovirus Infection levels were significantly lower in wild-type C57BL/6 mice than in Tetherin knockout mice at 2 wk postInfection, and antiretroviral protection correlated with stronger NK cell and virus-specific CD8+ T cell responses. The results demonstrate that Tetherin acts as a modulator of the cell-mediated immune response against Retrovirus Infection in vivo.
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il 2 independent and tnf α dependent expansion of vβ5 natural regulatory t cells during Retrovirus Infection
Journal of Immunology, 2013Co-Authors: Lara Myers, Ronald J Messer, George Kassiotis, Ulf Dittmer, Aaron B Carmody, Jara J Joedicke, Jaquelin P Dudley, Kim J. HasenkrugAbstract:Friend virus Infection of mice induces the expansion and activation of regulatory T cells (Tregs) that dampen acute immune responses and promote the establishment and maintenance of chronic Infection. Adoptive transfer experiments and the expression of neuropilin-1 indicate that these cells are predominantly natural Tregs rather than virus-specific conventional CD4 + T cells that converted into induced Tregs. Analysis of Treg TCR Vβ chain usage revealed a broadly distributed polyclonal response with a high proportionate expansion of the Vβ5 + Treg subset, which is known to be responsive to endogenous Retrovirus-encoded superantigens. In contrast to the major population of Tregs, the Vβ5 + subset expressed markers of terminally differentiated effector cells, and their expansion was associated with the level of the antiviral CD8 + T cell response rather than the level of Friend virus Infection. Surprisingly, the expansion and accumulation of the Vβ5 + Tregs was IL-2 independent but dependent on TNF-α. These experiments reveal a subset-specific Treg induction by a new pathway.
Gennadiy Zelinskyy - One of the best experts on this subject based on the ideXlab platform.
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granulocytic myeloid derived suppressor cells suppress virus specific cd8 t cell responses during acute friend Retrovirus Infection
Retrovirology, 2017Co-Authors: Malgorzata Drabczykpluta, Ulf Dittmer, Tanja Werner, Daniel Hoffmann, Qibin Leng, Lieping Chen, Gennadiy ZelinskyyAbstract:Myeloid-derived suppressor cells (MDSCs) can suppress T cell responses in several different diseases. Previously these suppressive cells were observed to expand in HIV patients and in a mouse Retrovirus model, yet their suppressive effect on virus-specific CD8+ T cells in vitro and in vivo has not been characterized thus far. We used the Friend Retrovirus (FV) model to demonstrate that MDSCs expand and become activated during the late phase of acute FV Infection. Only the subpopulation of granulocytic MDSCs (gMDSCs) but not monocytic MDSC suppressed virus-specific CD8+ T cell proliferation and function in vitro. gMDSCs expressed arginase 1, high levels of the inhibitory ligand PD-L1 and the ATP dephosphorylating enzyme CD39 on the cell surface upon Infection. All three molecules were involved in the suppressive effect of the gMDSCs in vitro. MDSC depletion experiments in FV-infected mice revealed that they restrict virus-specific CD8+ T cell responses and thus affect the immune control of chronic Retroviruses in vivo. Our study demonstrates that MDSCs become activated and expand during the acute phase of Retrovirus Infection. Their suppressive activity on virus-specific CD8+ T cells may contribute to T cell dysfunction and the development of chronic Infection.
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fas ligand mediated cytotoxicity of cd4 t cells during chronic Retrovirus Infection
Scientific Reports, 2017Co-Authors: A I Malyshkina, Kim J. Hasenkrug, Gennadiy Zelinskyy, Simone Schimmer, Elisabeth Littwitzsalomon, Kathrin Sutter, Sonja Windmann, Annette Paschen, Hendrik Streeck, Ulf DittmerAbstract:CD4+ helper T cells and cytotoxic CD8+ T cells are key players for adaptive immune responses against acute Infections with Retroviruses. Similar to textbook knowledge the most important function of CD4+ T cells during an acute Retrovirus Infection seems to be their helper function for other immune cells. Whereas there was no direct anti-viral activity of CD4+ T cells during acute Friend Virus (FV) Infection, they were absolutely required for the control of chronic Infection. During chronic FV Infection a population of activated FV-specific CD4+ T cells did not express cytotoxic molecules, but Fas Ligand that can induce Fas-induced apoptosis in target cells. Using an MHC II-restricted in vivo CTL assay we demonstrated that FV-specific CD4+ T cells indeed mediated cytotoxic effects against FV epitope peptide loaded targets. CD4 + CTL killing was also detected in FV-infected granzyme B knockout mice confirming that the exocytosis pathway was not involved. However, killing could be blocked by antibodies against FasL, which identified the Fas/FasL pathway as critical cytotoxic mechanism during chronic FV Infection. Interestingly, targeting the co-stimulatory receptor CD137 with an agonistic antibody enhanced CD4+ T cell cytotoxicity. This immunotherapy may be an interesting new approach for the treatment of chronic viral Infections.
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the phenotype and activation status of regulatory t cells during friend Retrovirus Infection
Virologica Sinica, 2014Co-Authors: Jara J Joedicke, Kirsten K Dietze, Gennadiy Zelinskyy, Ulf DittmerAbstract:The suppressive capacity of regulatory T cells (Tregs) has been extensively studied and is well established for many diseases. The expansion, accumulation, and activation of Tregs in viral Infections are of major interest in order to find ways to alter Treg functions for therapeutic benefit. Tregs are able to dampen effector T cell responses to viral Infections and thereby contribute to the establishment of a chronic Infection. In the Friend Retrovirus (FV) mouse model, Tregs are known to expand in all infected organs. To better understand the characteristics of these Treg populations, their phenotype was analyzed in detail. During acute FV-Infection, Tregs became activated in the spleen and bone marrow, as indicated by various T cell activation markers, such as CD43 and CD103. Interestingly, Tregs in the bone marrow, which contains the highest viral loads during acute Infection, displayed greater levels of activation than Tregs from the spleen. Treg expansion was driven by proliferation but no FV-specific Tregs could be detected. Activated Tregs in FV-Infection did not produce Granzyme B (GzmB) or tumor necrosis factor α (TNFα), which are thought to be a potential mechanism for their suppressive activity. Furthermore, Tregs expressed inhibitory markers, such as TIM3, PD-1 and PD-L1. Blocking TIM3 and PD-L1 with antibodies during chronic FV-Infection increased the numbers of activated Tregs. These data may have important implications for the understanding of Treg functions during chronic viral Infections.
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virus specific cd8 t cells upregulate programmed death 1 expression during acute friend Retrovirus Infection but are highly cytotoxic and control virus replication
Journal of Immunology, 2011Co-Authors: Gennadiy Zelinskyy, Kim J. Hasenkrug, Kathrin Gibbert, Lara Myers, Kirsten K Dietze, Michael Roggendorf, Jia Liu, Anke R M Kraft, Volker Teichgraber, Ulf DittmerAbstract:It was recently reported that inhibitory molecules such as programmed death-1 (PD-1) were upregulated on CD8(+) T cells during acute Friend Retrovirus Infection and that the cells were prematurely exhausted and dysfunctional in vitro. The current study confirms that most activated CD8(+) T cells upregulated expression of PD-1 during acute Infection and revealed a dichotomy of function between PD-1(hi) and PD-1(lo) subsets. More PD-1(lo) cells produced antiviral cytokines such as IFN-γ and TNF-α, whereas more PD-1(hi) cells displayed characteristics of cytotoxic effectors such as production of granzymes and surface expression of CD107a. Importantly, CD8(+) T cells mediated rapid in vivo cytotoxicity and were critical for control of acute Friend virus replication. Thus, direct ex vivo analyses and in vivo experiments revealed high CD8(+) T cell functionality and indicate that PD-1 expression during acute Infection is not a marker of T cell exhaustion.
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kinetics of cd8 effector t cell responses and induced cd4 regulatory t cell responses during friend Retrovirus Infection
European Journal of Immunology, 2006Co-Authors: Gennadiy Zelinskyy, Simone Schimmer, Anke R M Kraft, Tanja Arndt, Ulf DittmerAbstract:Cytolytic CD8+ T cells are critical for the control of acute Friend virus (FV) Infection yet they fail to completely eliminate the virus during chronic Infection because they are functionally impaired by regulatory T cells (Treg). We performed a kinetic analysis of T cell responses during FV Infection to determine when dysfunction of CD8+ T cells and suppressive activity of CD4+ regulatory T cells develops. At 1 week post Infection, virus-specific CD8+ T cells with effector phenotype and cytolytic potential expanded. Peak expansion was found at 12 days post Infection, correlating with peak viral loads. After 2 weeks when viral loads dropped, numbers of activated CD8+ T cells started to decline. However, a population of virus-specific CD8+ T cells with effector phenotype was still detectable subsequently, but these cells had lost their ability to produce granzymes and to degranulate cytotoxic molecules. Contemporaneous with the development of CD8+ T cell dysfunction, different CD4+ T cell populations expressing cell surface markers for Treg and the Treg-associated transcription factor Foxp3 expanded. Transfer as well as depletion experiments indicated that regulatory CD4+ cells developed during the second week of FV Infection and subsequently suppressed CD8+ T cell functions, which was associated with impaired virus clearance.
Ronald J Messer - One of the best experts on this subject based on the ideXlab platform.
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b cell requirement for robust regulatory t cell responses to friend Retrovirus Infection
Mbio, 2017Co-Authors: Tyler C Moore, Ronald J Messer, Lorena M Gonzaga, Jennifer M Mather, Kim J. HasenkrugAbstract:Regulatory T cells (Tregs) are immunosuppressive cells of the immune system that control autoimmune reactivity. Tregs also respond during immune reactions to infectious agents in order to limit immunopathological damage from potent effectors such as CD8+ cytolytic T lymphocytes. We have used the Friend virus (FV) model of retroviral Infection in mice to investigate how viral Infections induce Tregs. During acute FV Infection, there is significant activation and expansion of thymus-derived (natural) Tregs that suppress virus-specific CD8+ T cell responses. Unlike conventional T cells, the responding Tregs are not virus specific, so the mechanisms that induce their expansion are of great interest. We now show that B cells provide essential signals for Treg expansion during FV Infection. Treg responses are greatly diminished in B cell-deficient mice but can be restored by adoptive transfers of B cells at the time of Infection. The feeble Treg responses in B cell-deficient mice are associated with enhanced virus-specific CD8+ T cell responses and accelerated virus control during the first 2 weeks of Infection. In vitro experiments demonstrated that B cells promote Treg activation and proliferation through a glucocorticoid-induced receptor superfamily member 18 (GITR) ligand-dependent mechanism. Thus, B cells play paradoxically opposing roles during FV Infection. They provide proliferative signals to immunsosuppressive Tregs, which slows early virus control, and they also produce virus-specific antibodies, which are essential for long-term virus control.IMPORTANCE When infectious agents invade a host, numerous immunological mechanisms are deployed to limit their replication, neutralize their spread, and destroy the host cells harboring the Infection. Since immune responses also have a strong capacity to damage host cells and tissues, their magnitude, potency, and duration are under regulatory control. Regulatory T cells are an important component of this control, and the mechanisms that induce them to respond and exert immunosuppressive regulation are of great interest. In the current report, we show that B cells, the cells responsible for making pathogen-specific antibodies, are also involved in promoting the expansion of regulatory T cells during a retroviral Infection. In vitro studies demonstrated that they do so via stimulation of the Tregs through interactions between cell surface molecules: GITR interactions with its ligand (GITRL) on B cells and GITR on regulatory T cells. These findings point the way toward therapeutics to better treat Infections and autoimmune diseases.
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tetherin promotes the innate and adaptive cell mediated immune response against Retrovirus Infection in vivo
Journal of Immunology, 2014Co-Authors: Bradley S Barrett, Karl J Heilman, Kim J. Hasenkrug, Ronald J Messer, Rachel A. Liberatore, George Kassiotis, Mario L SantiagoAbstract:Tetherin/BST-2 is a host restriction factor that could directly inhibit retroviral particle release by tethering nascent virions to the plasma membrane. However, the immunological impact of Tetherin during Retrovirus Infection remains unknown. We now show that Tetherin influences antiretroviral cell-mediated immune responses. In contrast to the direct antiviral effects of Tetherin, which are dependent on cell surface expression, the immunomodulatory effects are linked to the endocytosis of the molecule. Mice encoding endocytosis-competent C57BL/6 Tetherin exhibited lower viremia and pathology at 7 d postInfection with Friend Retrovirus (FV) compared with mice encoding endocytosis-defective NZW/LacJ Tetherin. Notably, antiretroviral protection correlated with stronger NK cell responses. In addition, Friend Retrovirus Infection levels were significantly lower in wild-type C57BL/6 mice than in Tetherin knockout mice at 2 wk postInfection, and antiretroviral protection correlated with stronger NK cell and virus-specific CD8+ T cell responses. The results demonstrate that Tetherin acts as a modulator of the cell-mediated immune response against Retrovirus Infection in vivo.
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il 2 independent and tnf α dependent expansion of vβ5 natural regulatory t cells during Retrovirus Infection
Journal of Immunology, 2013Co-Authors: Lara Myers, Ronald J Messer, George Kassiotis, Ulf Dittmer, Aaron B Carmody, Jara J Joedicke, Jaquelin P Dudley, Kim J. HasenkrugAbstract:Friend virus Infection of mice induces the expansion and activation of regulatory T cells (Tregs) that dampen acute immune responses and promote the establishment and maintenance of chronic Infection. Adoptive transfer experiments and the expression of neuropilin-1 indicate that these cells are predominantly natural Tregs rather than virus-specific conventional CD4 + T cells that converted into induced Tregs. Analysis of Treg TCR Vβ chain usage revealed a broadly distributed polyclonal response with a high proportionate expansion of the Vβ5 + Treg subset, which is known to be responsive to endogenous Retrovirus-encoded superantigens. In contrast to the major population of Tregs, the Vβ5 + subset expressed markers of terminally differentiated effector cells, and their expansion was associated with the level of the antiviral CD8 + T cell response rather than the level of Friend virus Infection. Surprisingly, the expansion and accumulation of the Vβ5 + Tregs was IL-2 independent but dependent on TNF-α. These experiments reveal a subset-specific Treg induction by a new pathway.
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effects of acute and chronic murine norovirus Infections on immune responses and recovery from friend Retrovirus Infection
Journal of Virology, 2009Co-Authors: Christoph G Ammann, Ronald J Messer, Kimberly Varvel, Blair L Debuysscher, Rachel Lacasse, Amelia K Pinto, Kim J. HasenkrugAbstract:Murine norovirus (MNV) is a highly infectious but generally nonpathogenic agent that is commonly found in research mouse colonies in both North America and Europe. In the present study, the effects of acute and chronic Infections with MNV on immune responses and recovery from concurrent Friend virus (FV) Infections were investigated. No significant differences in T-cell or NK-cell responses, FV-neutralizing antibody responses, or long-term recovery from FV Infection were observed. We conclude that concurrent MNV Infections had no major impacts on FV Infections.
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apobec3 encodes rfv3 a gene influencing neutralizing antibody control of Retrovirus Infection
Science, 2008Co-Authors: Mario L Santiago, Kim J. Hasenkrug, Ronald J Messer, Bruce Chesebro, Mauricio Montano, Robert Benitez, Wes Yonemoto, Warner C GreeneAbstract:Recovery from Friend virus 3 (Rfv3) is a single autosomal gene encoding a resistance trait that influences retroviral neutralizing antibody responses and viremia. Despite extensive research for 30 years, the molecular identity of Rfv3 has remained elusive. Here, we demonstrate that Rfv3 is encoded by Apobec3. Apobec3 maps to the same chromosome region as Rfv3 and has broad inhibitory activity against Retroviruses, including HIV. Not only did genetic inactivation of Apobec3 convert Rfv3-resistant mice to a susceptible phenotype, but Apobec3 was also found to be naturally disabled by aberrant messenger RNA splicing in Rfv3-susceptible strains. The link between Apobec3 and neutralizing antibody responses highlights an Apobec3-dependent mechanism of host protection that might extend to HIV and other human retroviral Infections.
Steve Best - One of the best experts on this subject based on the ideXlab platform.
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positional cloning of the mouse Retrovirus restriction gene fv1
Nature, 1996Co-Authors: Paul Le Tissier, Steve Best, Greg J Towers, Jonathan Paul StoyeAbstract:VERTEBRATE evolution has taken place against a background of constant Retrovirus Infection, and much of the mammalian genome consists of endogenous Retrovirus-like elements1. Several host genes have evolved to control Retrovirus replication2, including Friend-virus-susceptibility-1, Fv1, on mouse chromosome 4 (refs 3, 4). The Fv1 gene acts on murine leukaemia virus at a stage after entry into the target cell but before integration and formation of the provirus5. Although restriction is not absolute, Fv1 prevents or delays spontaneous or experimentally induced viral tumours2. In vitro, Fv1 restriction leads to an apparent 50–1,000 fold reduction in viral titre6. Genetic evidence implicates a direct interaction between the Fv1 gene product and a component of the viral preintegration complex, the capsid protein CA (refs 7–9). We have now cloned Fv1: the gene appears to be derived from the gag region of an endogenous Retrovirus unrelated to murine leukaemia virus, implying that the Fv1 protein and its target may share functional similarities despite the absence of nucleotide-sequence homology.
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positional cloning of the mouse Retrovirus restriction gene fv1
Nature, 1996Co-Authors: Steve Best, Paul Le Tissier, Greg J Towers, Jonathan P StoyeAbstract:VERTEBRATE evolution has taken place against a background of constant Retrovirus Infection, and much of the mammalian genome consists of endogenous Retrovirus-like elements1. Several host genes have evolved to control Retrovirus replication2, including Friend-virus-susceptibility-1, Fv1, on mouse chromosome 4 (refs 3, 4). The Fv1 gene acts on murine leukaemia virus at a stage after entry into the target cell but before integration and formation of the provirus5. Although restriction is not absolute, Fv1 prevents or delays spontaneous or experimentally induced viral tumours2. In vitro, Fv1 restriction leads to an apparent 50–1,000 fold reduction in viral titre6. Genetic evidence implicates a direct interaction between the Fv1 gene product and a component of the viral preintegration complex, the capsid protein CA (refs 7–9). We have now cloned Fv1: the gene appears to be derived from the gag region of an endogenous Retrovirus unrelated to murine leukaemia virus, implying that the Fv1 protein and its target may share functional similarities despite the absence of nucleotide-sequence homology.