Feline Immunodeficiency Virus Infection Phenotypically and Functionally Activates Immunosuppressive CD4+CD25+ T Regulatory Cells

Vahlenkamp, Thomas W.; Tompkins, Mary B.; Tompkins, W. A. F.

doi:10.4049/jimmunol.172.8.4752

Cited by 96 publications

(104 citation statements)

References 62 publications

(55 reference statements)

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“…In our in vitro assay, FVinduced Tregs demonstrated suppressive activity directly ex vivo. This finding is consistent with studies of the hepatitis C virus (64) and the feline immunodeficiency virus (72) showing that virusinduced Tregs suppress in vitro without additional stimulation. This may be related to the higher activation status of virus-induced Treg as demonstrated by increased expression of activation markers such as CD69 (46), GITR (34, 38, 47), and LAG-3 (42).…”

Section: Discussionsupporting

confidence: 81%

In Vitro Suppression of CD8+ T Cell Function by Friend Virus-Induced Regulatory T Cells

Robertson

Messer

Carmody

et al. 2006

The Journal of Immunology

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Regulatory T cell (Treg)-mediated suppression of CD8+ T cells has been implicated in the establishment and maintenance of chronic viral infections, but little is known about the mechanism of suppression. In this study an in vitro assay was developed to investigate the suppression of CD8+ T cells by Friend retrovirus (FV)-induced Tregs. CD4+CD25+ T cells isolated from mice chronically infected with the FV suppressed the development of effector function in naive CD8+ T cells without affecting their ability to proliferate or up-regulate activation markers. In vitro restimulation was not required for suppression by FV-induced Tregs, correlating with their high activation state in vivo. Suppression was mediated by direct T cell-T cell interactions and occurred in the absence of APCs. Furthermore, suppression occurred irrespective of the TCR specificity of the CD8+ T cells. Most interestingly, FV-induced Tregs were able to suppress the function of CD8+ effector T cells that had been physiologically activated during acute FV infection. The ability to suppress the effector function of activated CTLs is likely a requisite role for Tregs in limiting immunopathology by CD8+ T cells during antiviral immune responses. Such activity may also have adverse consequences by allowing viruses to establish and maintain chronic infections if suppression of antiviral immune responses occurs before virus eradication.

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Section: Discussionsupporting

confidence: 81%

In Vitro Suppression of CD8+ T Cell Function by Friend Virus-Induced Regulatory T Cells

Robertson

Messer

Carmody

et al. 2006

The Journal of Immunology

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“…A number of microbial pathogens including viruses have been previously shown to increase the frequency of Tregs in infected tissues or lymphoid organs of adult mice and humans (12,(52)(53)(54)(55)(56). CD4 ϩ CD25 ϩ Tregs have been shown to suppress CD8 ϩ T effector function and activation to viruses including HSV and to viral vaccines in adult humans ex vivo, and in adult mice in vitro and in vivo (12,20,(53)(54)(55)(56)(57)(58)(59)(60). Enhanced Treg responses have been detected in the cord blood of human neonates born to women with Plasmodium falciparum infection compared with unexposed infants or infants born to mothers who had been treated for malaria (22).…”

Section: Discussionmentioning

confidence: 99%

T Regulatory Cells Contribute to the Attenuated Primary CD8+ and CD4+ T Cell Responses to Herpes Simplex Virus Type 2 in Neonatal Mice

Fernandez¹,

Puttur

Wang

et al. 2008

The Journal of Immunology

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The first weeks of life are characterized by immune tolerance and increased susceptibility to intracellular pathogens. The neonatal adaptive response to HSV is attenuated compared with adult control models in humans and mice. T Regulatory cells (Tregs) control autoimmunity and excessive immune responses to infection. We therefore compared Treg responses in the draining lymph nodes (LN) of HSV-infected neonatal and adult C57BL/6 mice with the effect of Treg depletion/inactivation by anti-CD25 (PC61) treatment before infection on Ag-specific T cell effector responses at this site. There was a small, but significant increase in the frequency of CD4+Foxp3+ Tregs at day 3 postinfection (p.i.) in the LN of neonatal and adult mice, compared with age-matched mock-infected controls. Depletion of Tregs before HSV infection significantly enhanced HSV-specific CD8+ T cell cytotoxicity in vivo, cell number, activation, and granzyme B expression 4 days p.i. only in neonatal mice, and significantly enhanced CD8+ and CD4+ T cell IFN-γ responses in both infected adults and neonates. Treg depletion also reduced the titer of infectious virus in the draining LN and nervous system of infected neonates on days 2 and 3 p.i. Treg suppression of the neonatal CTL response p.i. with HSV was associated with increased expression of TGF-β in the draining LN at day 4 p.i. compared with uninfected neonates, but IL-10 was increased in infected adults alone. These experiments support the notion that the newborn primary T cell effector responses to HSV are suppressed by Tregs.

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“…Thus, many viruses have developed mechanisms to evade immunological destruction by CTL to establish chronic infections. One evasion strategy, which has recently been described for several different viruses, is the induction of regulatory T cells (Treg) during infection [1][2][3][4]. Induced Treg can suppress antiviral CTL functions in vivo and contribute to persistent viral infections.…”

Section: Introductionmentioning

confidence: 99%

Kinetics of CD8⁺ effector T cell responses and induced CD4⁺ regulatory T cell responses during Friend retrovirus infection

Zelinskyy¹,

Kraft²,

Schimmer³

et al. 2006

Eur J Immunol

120

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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, virusspecific 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.

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Feline Immunodeficiency Virus Infection Phenotypically and Functionally Activates Immunosuppressive CD4+CD25+ T Regulatory Cells

Cited by 96 publications

References 62 publications

In Vitro Suppression of CD8+ T Cell Function by Friend Virus-Induced Regulatory T Cells

In Vitro Suppression of CD8+ T Cell Function by Friend Virus-Induced Regulatory T Cells

T Regulatory Cells Contribute to the Attenuated Primary CD8+ and CD4+ T Cell Responses to Herpes Simplex Virus Type 2 in Neonatal Mice

Kinetics of CD8⁺ effector T cell responses and induced CD4⁺ regulatory T cell responses during Friend retrovirus infection

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Feline Immunodeficiency Virus Infection Phenotypically and Functionally Activates Immunosuppressive CD4+CD25+ T Regulatory Cells

Cited by 96 publications

References 62 publications

In Vitro Suppression of CD8+ T Cell Function by Friend Virus-Induced Regulatory T Cells

In Vitro Suppression of CD8+ T Cell Function by Friend Virus-Induced Regulatory T Cells

T Regulatory Cells Contribute to the Attenuated Primary CD8+ and CD4+ T Cell Responses to Herpes Simplex Virus Type 2 in Neonatal Mice

Kinetics of CD8+ effector T cell responses and induced CD4+ regulatory T cell responses during Friend retrovirus infection

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Kinetics of CD8⁺ effector T cell responses and induced CD4⁺ regulatory T cell responses during Friend retrovirus infection