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

The role of FoxP3(+)CD4(+) regulatory T (Treg) cells in HIV-1 disease in vivo is poorly understood due to the lack of a robust model. We report here that CD4(+)FoxP3(+) T cells are developed in all lymphoid organs in humanized Rag2(-/-)gammaC(-/-) (DKO-hu HSC) mice and they display both Treg phenotype and Treg function. These FoxP3(+) Treg cells are preferentially infected and depleted by a pathogenic HIV-1 isolate in HIV-infected DKO-hu HSC mice; and depletion of Treg cells is correlated with induction of their apoptosis in vivo. When CD4(+)CD25(+/hi) Treg cells are depleted with the IL-2-toxin fusion protein (denileukin diftitox), HIV-1 infection is significantly impaired. This is demonstrated by reduced levels of productively infected cells in lymphoid organs and lower plasma viremia. Therefore, FoxP3(+) Treg cells are productively infected and play an important role in acute HIV-1 infection in vivo. The DKO-hu HSC mouse will be a valuable model to study human Treg functions and their role in HIV-1 pathogenesis in vivo.

[1]  S. Kalams,et al.  Naive Precursors of Human Regulatory T Cells Require FoxP3 for Suppression and Are Susceptible to HIV Infection1 , 2008, The Journal of Immunology.

[2]  T. Curiel,et al.  IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity. , 2007, Blood.

[3]  L. Su,et al.  FoxP3 Enhances HIV-1 Gene Expression by Modulating NFκB Occupancy at the Long Terminal Repeat in Human T Cells* , 2007, Journal of Biological Chemistry.

[4]  G. Kovalev,et al.  HIV-1 infection and pathogenesis in a novel humanized mouse model. , 2007, Blood.

[5]  L. Picker,et al.  Simian Immunodeficiency Virus (SIV) Infection Influences the Level and Function of Regulatory T Cells in SIV-Infected Rhesus Macaques but Not SIV-Infected Sooty Mangabeys , 2007, Journal of Virology.

[6]  C. Chougnet,et al.  HIV-1-driven regulatory T-cell accumulation in lymphoid tissues is associated with disease progression in HIV/AIDS. , 2006, Blood.

[7]  A. Haase,et al.  Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1 , 2006, Nature Medicine.

[8]  H. Stein,et al.  Mucosal but not peripheral FOXP3+ regulatory T cells are highly increased in untreated HIV infection and normalize after suppressive HAART. , 2006, Blood.

[9]  B. Palmer,et al.  HIV-1 infection and CD4 T cell depletion in the humanized Rag2-/-γc-/- (RAG-hu) mouse model , 2006, Retrovirology.

[10]  Shibo Jiang,et al.  Fusion-Induced Apoptosis Contributes to Thymocyte Depletion by a Pathogenic Human Immunodeficiency Virus Type 1 Envelope in the Human Thymus , 2006, Journal of Virology.

[11]  Markus G. Manz,et al.  Disseminated and sustained HIV infection in CD34+ cord blood cell-transplanted Rag2−/−γc−/− mice , 2006, Proceedings of the National Academy of Sciences.

[12]  J. Stroud,et al.  FOXP3 Controls Regulatory T Cell Function through Cooperation with NFAT , 2006, Cell.

[13]  Whitney S. Helms,et al.  Delayed functional maturation of natural regulatory T cells in the medulla of postnatal thymus: role of TSLP , 2006, BMC Immunology.

[14]  D. Watkins,et al.  Premature induction of an immunosuppressive regulatory T cell response during acute simian immunodeficiency virus infection. , 2006, The Journal of infectious diseases.

[15]  J. Kaye,et al.  Commitment issues: linking positive selection signals and lineage diversification in the thymus , 2006, Immunological reviews.

[16]  E. Gilboa,et al.  Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. , 2005, The Journal of clinical investigation.

[17]  V. Godfrey,et al.  The Scurfy mutation of FoxP3 in the thymus stroma leads to defective thymopoiesis , 2005, The Journal of experimental medicine.

[18]  Yu Wang,et al.  Hassall's corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus , 2005, Nature.

[19]  P. Massip,et al.  FOXP3 mRNA Levels are Decreased in Peripheral Blood CD4+ Lymphocytes From HIV-Positive Patients , 2005, Journal of acquired immune deficiency syndromes.

[20]  S. Higasa,et al.  Relationship of CD4+CD25+ regulatory T cells to immune status in HIV-infected patients , 2005, AIDS.

[21]  L. Su,et al.  Thymic pathogenicity of an HIV-1 envelope is associated with increased CXCR4 binding efficiency and V5-gp41-dependent activity, but not V1/V2-associated CD4 binding efficiency and viral entry. , 2005, Virology.

[22]  E. Bettelli,et al.  Foxp3 interacts with nuclear factor of activated T cells and NF-kappa B to repress cytokine gene expression and effector functions of T helper cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[23]  N. Jones,et al.  Depletion of Regulatory T Cells in HIV Infection Is Associated with Immune Activation1 , 2005, The Journal of Immunology.

[24]  William J. Kaiser,et al.  Divergent Host Responses during Primary Simian Immunodeficiency Virus SIVsm Infection of Natural Sooty Mangabey and Nonnatural Rhesus Macaque Hosts , 2005, Journal of Virology.

[25]  Yasmine Belkaid,et al.  Natural regulatory T cells in infectious disease , 2005, Nature Immunology.

[26]  N. Shire,et al.  Cutting Edge: The Prevalence of Regulatory T Cells in Lymphoid Tissue Is Correlated with Viral Load in HIV-Infected Patients 1 , 2005, The Journal of Immunology.

[27]  Y. Lévy,et al.  Human immunodeficiency virus-driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients. , 2004, Blood.

[28]  F. Gao,et al.  Characterization of a thymus-tropic HIV-1 isolate from a rapid progressor: role of the envelope. , 2004, Virology.

[29]  George Coukos,et al.  Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival , 2004, Nature Medicine.

[30]  S. Ziegler,et al.  CD25+CD4+ Regulatory T Cells from the Peripheral Blood of Asymptomatic HIV-infected Individuals Regulate CD4+ and CD8+ HIV-specific T Cell Immune Responses In Vitro and Are Associated with Favorable Clinical Markers of Disease Status , 2004, The Journal of experimental medicine.

[31]  Mark S. Sundrud,et al.  HIV Infection of Naturally Occurring and Genetically Reprogrammed Human Regulatory T-cells , 2004, PLoS biology.

[32]  H. von Boehmer,et al.  In Vivo Instruction of Suppressor Commitment in Naive T Cells , 2004, The Journal of experimental medicine.

[33]  J. Piette,et al.  CD4+CD25+ regulatory T-cell deficiency in patients with hepatitis C-mixed cryoglobulinemia vasculitis. , 2004, Blood.

[34]  P. V. van Eeden,et al.  Timed Ablation of Regulatory CD4+ T Cells Can Prevent Murine AIDS Progression , 2004, The Journal of Immunology.

[35]  W. Tompkins,et al.  Preferential replication of FIV in activated CD4(+)CD25(+)T cells independent of cellular proliferation. , 2004, Virology.

[36]  Markus G. Manz,et al.  Development of a Human Adaptive Immune System in Cord Blood Cell-Transplanted Mice , 2004, Science.

[37]  S. Sakaguchi.  Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. , 2004, Annual review of immunology.

[38]  P. Greenberg,et al.  Functional impairment of CD8(+) T cells by regulatory T cells during persistent retroviral infection. , 2004, Immunity.

[39]  Li Li,et al.  Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3 , 2003, The Journal of experimental medicine.

[40]  K. Sugimoto,et al.  Suppression of HCV‐specific T cells without differential hierarchy demonstrated ex vivo in persistent HCV infection , 2003, Hepatology.

[41]  F. Ramsdell,et al.  An essential role for Scurfin in CD4+CD25+ T regulatory cells , 2003, Nature Immunology.

[42]  A. Rudensky,et al.  Foxp3 programs the development and function of CD4+CD25+ regulatory T cells , 2003, Nature Immunology.

[43]  R. Koup,et al.  Nonpathogenic SIV infection of sooty mangabeys is characterized by limited bystander immunopathology despite chronic high-level viremia. , 2003, Immunity.

[44]  S. Hori,et al.  Supporting Online Material , 2002 .

[45]  Y. Belkaid,et al.  CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity , 2002, Nature.

[46]  S. Morse,et al.  Virus and autoimmunity: induction of autoimmune disease in mice by mouse T lymphotropic virus (MTLV) destroying CD4+ T cells. , 1999, Journal of immunology.

[47]  L. Su.  HIV‐1 pathogenesis and therapeutic intervention in the SCID‐hu Thy/Liv mouse: a model for primary HIV‐1 infection in the human thymus , 1997, Reviews in medical virology.

[48]  M. Roncarolo,et al.  Anti-SCID mouse reactivity shapes the human CD4+ T cell repertoire in hu-PBL-SCID chimeras , 1994, The Journal of experimental medicine.

[49]  R. Detels,et al.  Elevated levels of CD38+ CD8+ T cells in HIV infection add to the prognostic value of low CD4+ T cell levels: results of 6 years of follow-up. The Los Angeles Center, Multicenter AIDS Cohort Study. , 1993, Journal of acquired immune deficiency syndromes.

[50]  I. Weissman,et al.  The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. , 1988, Science.

[51]  Donald E. Mosier,et al.  Transfer of a functional human immune system to mice with severe combined immunodeficiency , 1988, Nature.

[52]  E. Shevach,et al.  Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy. , 2004, Immunity.

[53]  D. Galas,et al.  Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse , 2001, Nature Genetics.

[54]  H. Ochs,et al.  The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3 , 2001, Nature Genetics.

[55]  D. Kraft,et al.  HIV-1-induced thymocyte depletion is associated with indirect cytopathogenicity and infection of progenitor cells in vivo. , 1995, Immunity.