FoxP3+CD4+ regulatory T cells play an important role in acute HIV-1 infection in humanized Rag2−/−γC−/− mice in vivo

Jiang, Qi; Zhang, Liguo; Wang, Rui; Jeffrey, Jerry; Washburn, Michael L.; Brouwer, Dedeke; Barbour, Selena; Kovalev, Grigoriy I.; Unutmaz, Derya; Su, Lishan

doi:10.1182/blood-2008-03-145946

Cited by 94 publications

(113 citation statements)

References 54 publications

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“…48,49 In this context, the results of the present study suggest that, because of their immunomodulatory actions, mAb-based immunotherapies directed to viral antigens may constitute invaluable tools with which to combat the deleterious effect of Tregs in chronic viral infection. Because Tregs can suppress anticancer immune responses 50 and because mAb immunotherapies targeting tumor cell-surface molecules may enhance anticancer immune responses, 25,26 our findings may also have applications in the treatment of cancer.…”

Section: Discussionmentioning

confidence: 98%

Control of regulatory T cells is necessary for vaccine-like effects of antiviral immunotherapy by monoclonal antibodies

Nasser

Pelegrin

Plays

et al. 2013

Blood

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Key Points• Mab-based immunotherapy prevents Treg expansion and limits immunosuppressive activity.Regulatory T cells (Tregs) down-regulate immunity and are associated with chronic viral infections, suggesting that their inhibition might be used to treat life-threatening diseases. Using the FrCas E mouse retroviral model, we have recently shown that short mAb-based immunotherapies can induce life-long protective immunity. This finding has a potentially important therapeutical impact because mAbs are increasingly used to treat severe viral infections. We now report that poor anti-FrCas E immunity in infected mice is due to Treg expansion in secondary lymphoid organs because depletion of Tregs restored humoral and cytotoxic T lymphocyte (CTL) antiviral responses. Kinetic analyses show that Treg expansion is not a consequence of chronicity, but rather is associated with viral spread. Moreover, Treg adoptive transfers indicate that production of the immunosuppressive cytokine IL-10 is essential for preventing a protective immune response. Finally, treatment of infected mice with a virus-neutralizing IgG2a shortly after infection prevents Treg expansion and limits immunosuppressive activity. This effect is rapid, necessary for the development of protective immunity, and depends on mAb effector functions. Therefore, manipulating Tregs may be necessary to confer robust antiviral immunity in the context of mAb-based therapy. This concept likely applies to cancer treatment because vaccine-like effects of mAbs have also been observed in certain cancer immunotherapies. (Blood. 2013;121(7):1102-1111) IntroductionRegulatory T cells (Tregs) are a subset of CD4 ϩ T lymphocytes down-regulating the immune system. 1 They are the key modulators of the establishment and/or maintenance of viral chronicity and constitute a barrier to efficient vaccination and immunotherapy strategies. 2 The implication of Tregs in chronic viral infection was first described in mice infected with the Friend virus complex (FV) 3 and was then extended to other persistent viruses, including HIV, 4 HBV, 5,6 HCV, 5,6 EBV, 7 LCMV, 8 HSV, 9 and HPVs. 10 It is increasingly clear that controlling this immunosuppressive cell subset would have widespread clinical applications to fight lifethreatening viral diseases. 11 mAbs constitute the largest class of biotherapeutics. 12 Their main current applications are in cancer and inflammatory diseases, 12 but they also have an enormous potential to treat both acute and chronic severe viral infections. Although the first antiviral mAb to be commercialized (in 1998) was an anti-RSV to treat an infant respiratory disease, 13 many of the current antiviral mAbs have been developed more recently. 12 Illustrating this trend, humanized mAbs targeting diverse viruses (Ebola, WNV, CMV, human and avian influenza, SARS, Hanta, and Nipah) responsible for acute diseases have recently shown promising results in preclinical animal settings. Some of them are now undergoing clinical trials. 14 Many chronic infections have also been targ...

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Section: Discussionmentioning

confidence: 98%

Control of regulatory T cells is necessary for vaccine-like effects of antiviral immunotherapy by monoclonal antibodies

Nasser

Pelegrin

Plays

et al. 2013

Blood

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“…It was reported previously that approximately 1%-4% of human CD4 ϩ T cells present in thymus, spleen, lymph nodes, and blood of humanized BRG (BALB/c Rag2 Ϫ/Ϫ IL2R␥ null ) mice display both T reg phenotype (CD25 ϩ FoxP3 ϩ ) and T reg function. 38 In NSG recipients, human CD4 ϩ T cells preferentially develop into Th1 cells, although Th2 and Th17 cells are also generated. 11 Here, we confirm these observations in both HIS and HIS-SGM3 mice and additionally provide evidence that human CD4 ϩ FoxP3 ϩ regulatory T cells also develop in both strains, albeit at significantly increased frequencies in HIS-SGM3 recipients.…”

Section: Discussionmentioning

confidence: 99%

Development of human CD4+FoxP3+ regulatory T cells in human stem cell factor–, granulocyte-macrophage colony-stimulating factor–, and interleukin-3–expressing NOD-SCID IL2Rγnull humanized mice

Billerbeck

Barry

et al. 2011

Blood

265

232

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Human hematolymphoid mice have become valuable tools for the study of human hematopoiesis and uniquely human pathogens in vivo. Recent improvements in xenorecipient strains allow for longterm reconstitution with a human immune system. However, certain hematopoietic lineages, for example, the myeloid lineage, are underrepresented, possibly because of the limited cross-reactivity of murine and human cytokines. Therefore, we created a nonobese diabetic/severe combined immunodeficiency/interleukin-2 receptor-␥-null (NOD-SCID IL2R␥ null ) mouse strain that expressed human stem cell factor, granulocyte-macrophage colonystimulating factor, and interleukin-3, termed NSG-SGM3. Transplantation of CD34 ؉ human hematopoietic stem cells into NSG-SGM3 mice led to robust human hematopoietic reconstitution in blood, spleen, bone marrow, and liver. Human myeloid cell frequencies, specifically, myeloid dendritic cells, were elevated in the bone marrow of humanized NSG-SGM3 mice compared with nontransgenic NSG recipients. Most significant, however, was the increase in the CD4 ؉ FoxP3 ؉ regulatory T-cell population in all compartments analyzed. These CD4 ؉ FoxP3 ؉ regulatory T cells were functional, as evidenced by their ability to suppress T-cell proliferation. In conclusion, humanized NSG-SGM3 mice might serve as a useful model to study human regulatory T-cell development in vivo, but this unexpected lineage skewing also highlights the importance of adequate spatiotemporal expression of human cytokines for future xenorecipient strain development. (Blood. 2011;117(11): 3076-3086) IntroductionHumanized mice are amenable small-animal models that have been transplanted with human cells or tissues (and/or equipped with human transgenes). In particular, animals conditioned to support engraftment of human immune cells have emerged as powerful tools for analysis of human hematopoiesis and the study of pathogens with unique human tropism. From the earliest attempts to engraftment of human immune cells in mice in the late 1980s, the field has progressed substantially, and improved, highly immunocompromised xenorecipient strains now allow for high-level engraftment of human immune cells. Currently, the most advanced strains are the nonobese diabetic, severe combined immunodeficiency (NOD-SCID) mouse with either truncated (NOG) or complete (NSG) disruptions in the interleukin-2 (IL-2) receptor common ␥-chain (IL2R␥ null ) and BALB/c Rag2 Ϫ/Ϫ IL2R␥ null (BRG) mice. 1 Injection of human hematopoietic stem cells (HSCs) isolated from human cord blood 2-5 or fetal liver tissue [5][6][7] results in robust engraftment of a human hematolymphoid system. Such human immune system (HIS) mice have opened new opportunities to analyze human immunity in vivo and to study pathogens with unique human tropism, including Epstein-Barr virus, HIV, and dengue virus. 8 However, current humanized mouse models have several shortcomings that must be overcome to advance toward a robust and predictive model for human immune responses. Specifically, the total amount of h...

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“…Humanized mouse models have been used widely to investigate the mechanisms of HIV-1 immunopathogenesis, including functionally defining the role of regulatory T cells (41), pDCs (30), and other cells (29) in acute and chronic HIV-1 infection. In the present study, we found that human ILC3 subsets were functionally developed in all lymphoid organs in NRG-hu mice and preferentially resided in the spleen and mLN.…”

Section: Discussionmentioning

confidence: 99%

Plasmacytoid dendritic cells promote HIV-1–induced group 3 innate lymphoid cell depletion

Zhang¹,

Liu²,

Zhao³

et al. 2015

Journal of Clinical Investigation

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FoxP3+CD4+ regulatory T cells play an important role in acute HIV-1 infection in humanized Rag2−/−γC−/− mice in vivo

Cited by 94 publications

References 54 publications

Control of regulatory T cells is necessary for vaccine-like effects of antiviral immunotherapy by monoclonal antibodies

Control of regulatory T cells is necessary for vaccine-like effects of antiviral immunotherapy by monoclonal antibodies

Development of human CD4+FoxP3+ regulatory T cells in human stem cell factor–, granulocyte-macrophage colony-stimulating factor–, and interleukin-3–expressing NOD-SCID IL2Rγnull humanized mice

Plasmacytoid dendritic cells promote HIV-1–induced group 3 innate lymphoid cell depletion

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