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Article · Volume 1, Issue 5, Pages 129–133, 12 September 2013 · Open Access

Regulatory T Cells in Avian Species

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Advances in Animal and Veterinary Sciences
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12 September 2013
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From the article

  • T regulatory cells (Tregs), a subset of T cells, specialize in immune suppression.
  • Increased hepatitis C virus (HCV)–specific CD4+CD25+ regulatory T lymphocytes and reduced HCV–specific CD4+ T cell response in HCV–infected patients with normal versus abnormal alanine aminotransferase levels.
  • In vivo depletion of CD4(+)CD25(hi) regulatory T cells is associated with improved antiviral responses in cats chronically infected with feline immunodeficiency virus.
  • Avian CD4 CD25 regulatory T cells: Properties and therapeutic applications.

Selected from the article's own text.

Abstract

Ramesh Kumar Selvaraj*, Revathi Shanmugasundaram
*Department of Animal Sciences, Ohio Agricultural Research and Development Center, Wooster, OH 44691. USA
*Corresponding author: selvaraj.7@osu.edu

Review Article

Advances in Animal and Veterinary Sciences 1 (5): 129 – 133

Regulatory T Cells in Avian Species

Ramesh Kumar Selvaraj*, Revathi Shanmugasundaram

    Department of Animal Sciences, Ohio Agricultural Research and Development Center, Wooster, OH 44691. USA

*Corresponding author:selvaraj.7@osu.edu

ARTICLE CITATION: Selvaraj RK (2013). Regulatory T cells in avian species. Adv. Anim. Vet. Sci. 1 (5): 129 – 133.
Received: 2013–07–16, Revised: 2013–08–02, Accepted: 2013–08–03
The electronic version of this article is the complete one and can be found online at ( http://nexusacademicpublishers.com/table_contents_detail/4/85/html ) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

INTRODUCTION

The immune system protects the host from foreign pathogens while avoiding damage towards self–antigens. T regulatory cells (Tregs), a subset of T cells, specialize in immune suppression. An adaptive immune response involves recruitment of effector (T and B) cells and Tregs. Activated immune cells, although essential for pathogen elimination, produce inflammatory cytokines and reactive oxygen species and can cause undesirable host damage . Tregs protect the host from an excessive immune response and maintain self tolerance and mucosal tolerance . The balance between the effector cells and Tregs is important for optimal immune responses, the proper control of immune responses, and for establishing tolerance to self–antigens. Disruption in function of Tregs is a primary cause of autoimmune and inflammatory diseases. On the other hand, hyperactive Tregs can impair T cell, B cell, and other immune cell functions and, therefore, are implicated in impaired microbial defenses, pathogen persistence , and impaired vaccine responses .

LACK OF UNIQUE MARKERS FOR TREGS

Among the different species in which Tregs have been characterized, human and mice Tregs have been extensively studied. Tregs constitutively express surface proteins like CD25, CD45, CTLA–4, HLA–DR, or GITR , but these markers are not present in Tregs of all species or exclusive to Tregs in any particular species. Among the markers that can be defined to be unique to Tregs, the most commonly used marker is FoxP3 . FoxP3, a transcription factor, is essential for development and function of mammalian Tregs . FoxP3 transcriptionally represses IL–2 and maintains suppressor functions of Tregs . Mutations in the FoxP3 gene cause autoimmune disease in scurfy mice and such mice succumb to autoimmune pathology . Though absence or mutations in FoxP3 gene results in impaired Treg functions, presence of FoxP3 genes does not necessarily confer suppressive properties. Human T cells transiently express FoxP3, without expressing the suppressive properties or cytokines characteristics of Tregs ; , though such T cells with transient FoxP3 expression with no suppressive properties are yet to be reported in other species. Our group reported that in chickens, CD4+CD25+ cells express suppressive properties even though in silico analysis failed to identify FoxP3 gene in the chicken genome .

PROPERTIES OF TREGS

There are several different categories of suppressive cells, namely T regulatory–1 cells (Tr1) , T helper 3 cells (Th3) , CD8+FoxP3+ , γδ T cells ; ; , natural killer T cells , and CD4–8–TCRαβ+ . The hall mark characteristics of CD4+25+ Tregs that differentiate CD4+25+ Tregs from the above mentioned suppressive populations are:

  1. CD4+25+ Tregs originate as a separate lineage of cells in the thymus .

  2. CD4+25+ Tregs are anergic (meaning they don’t proliferate) in vitro .

  3. CD4+25+ Tregs in vitro anergy and suppressive properties are reversed by exogenous IL–2 .

  4. CD4+25+ Tregs express CTLA–4, LAG–3 and PD–1 .

  5. CD4+25+ Tregs produce high amounts of IL–10 and low amounts of IL–2 ;

TREGS DYSREGULATION DURING INFECTIONS

Tregs are a central player in immune suppression. Tregs are the only cells that can directly suppress every other component of the immune system. Tregs can suppress T effector cells, dendritic cells , B cells , macrophages ( , NK cell (Frimpong–Boateng et al., 2010), mast cells , neutrophils and eosinophils . Given this “universal” action of Tregs, it is reasonable to assume that though Treg activity could be beneficial to the host, Tregs simultaneously inhibit host immunity and cause persistent infections. Treg dysregulation during persistent viral infections has been reviewed elegantly ; . During viral infections, T cell response leads to viral clearance. However, many viruses induce persistent infections despite continuous measurable T cell responses , a situation in which Tregs may be involved .

Tregs suppress the functions of CD4+ and CD8+ cells in the host and cause persistent infections of Friends virus ; , Vaccinia virus , Human Immunodeficiency virus ; , Hepatitis C virus ; , Hepatitis B virus ; , Human T Lymphotropic virus ; , Cytomegalovirus , and Feline Immunodeficiency virus . The influenza virus might have evolved to induce Tregs. Influenza–specific–Tregs suppress cytotoxic T lymphocytes by blocking CD8+ cell expansion. Tregs, stimulated with hemagglutinin antigen, expand more rapidly than CD8+ T cells and are highly suppressive in mice . In humans, Treg numbers increase while CD4+ cell numbers, B–lymphocytes numbers, and macrophage IFNγ and TNFα production decrease post H1N1 infection (Giamarellos–Bourboulis et al., 2009). Tregs inhibit proliferation and IFNγ production of influenza–specific CD8 in the local environment ; . Treg dysregulation is present during influenza A infection in mice . In chickens, CD4+CD25+ (Tregs) numbers increased following H9N2 avian influenza virus infection, but the authors could not explain the upregulated roles of Tregs during viral infection . The above studies strongly suggest the involvement of Tregs in augmenting the pathogenesis of avian influenza infections. Treg research with mammals suggests that the increase in Tregs percentage post–influenza infection might be a local effect rather than a systemic effect ; . Tregs reduce accumulation of macrophages in the lungs of influenza A virus–infected mice .

Tregs express several toll–like receptors (TLR), which recognize pathogen–associated molecular patterns . Tregs express TLR3, which recognizes double stranded RNA present during viral infections . TLR3–mediated activation amplifies the suppressive properties of Tregs . In addition, the host damage that occurs during infection and inflammation activates Tregs . Some pathogens have evolved to selectively induce Tregs ; and thereby impede host immune responses. Treg–mediated suppression of host immune cells prevents an effective immune response against pathogens. IL–10 and TGFβ produced by Tregs suppress CD8+ effector cells against viral pathogens . Tregs suppress IFNγ production by the host during an anti–viral response and thereby effectively impair the host defense against viral infections . The role of Tregs in depressing a host immune response during viral infections has been confirmed by experiments that selectively target or deplete Tregs during viral infections.

ENHANCED ANTI–VIRAL IMMUNE RESPONSE FOLLOWING TREG DEPLETION/ABLATION

Depletion of Tregs using anti–CD25 neutralizing antibody relieves the in vivo suppression of an antiviral immune response and contributes to faster oncolytic viral clearance . Depletion of Tregs enhances the activity of natural killer cells, activity of lymphokine–activated killer cells, and production of IFN . Treg ablation enhances the virus–specific CD8+ T cell numbers and production of IFN in the spleen of infected animal . Treg depletion results in reactivation of virus–specific T cells in chronically infected mice . In vitro, anti–IL–10 antibodies, which are expected to abrogate Treg functions , increase viral antigen–specific T cell proliferation .

TREGS OF AVIANS

Tregs have been extensively characterized in several animals like baboons , cows ; , pigs , cats , and rabbits . We earlier identified and characterized chicken CD4+CD25+ cells as Tregs in chickens . Similar to the CD25 expression in mammals (Baecher–Allan et al., 2001), CD25 expression in chicken thymic CD4+ cells was continuous in that cells express high, intermediate, or low levels of CD25, and the boundary between CD25high, CD25intermediate, and CD25low population is not clear . Chicken Tregs produce 29–fold higher IL–10 mRNA than non–Tregs. IL–10, an immunosuppressive cytokine, inhibits macrophages and dendritic cell functions and is a critical cytokine responsible for the suppressive properties of Tregs . Similar to chicken Tregs, ducks and turkey CD4+CD25+ cells had higher IL–10, TGF–β, CTLA–4, and LAG–3 mRNA amounts than CD4+CD25– cells from the respective species.

In chickens, Tregs initially appear at 16 d of embryonic development, and the first wave of Tregs preferentially migrates to the intestine . We identified that a single peritoneal injection of anti–chicken CD25 mAb decreases IL–10–producing Tregs in the intestine of chickens by approximately 80% . The depletion is temporary as Tregs return to their baseline levels at approximately 20 d post–CD25 injection. In ovo injection of 0.5 mg/egg of anti–chicken CD25 mAb at 16 d of embryonic development almost completely depleted circulating Tregs at hatch and that the birds remained depleted of Tregs until 25 d post–hatch. Chicks hatched from anti–chicken CD25–mAb–injected eggs had ~75% decrease in Tregs in the cecal tonsils at 16 d post–hatch . Chicks hatched from anti–chicken CD25 mAb injected eggs also had no detectable amount of Tregs in cecal tonsils at 0, 3, and 5 d post–hatch (unpublished observations).

We have also characterized chicken Tregs during Salmonella (a gut pathogen like coccidia) lipopolysaccharide–induced inflammation ; 2012c). The LPS injection increases CD4+CD25+ cell percentage approximately 2.5–fold in the spleen at 2 d post–LPS injection compared to the no–LPS–injected group, though the Treg numbers came back to normal levels at 5 d post–LPS injection . We evaluated the suppressive properties of chicken CD25+ cells from LPS injected or control groups. At a Treg: T responder cell ratio of 1:1, CD25+ cells only from 5 and 12d post–LPS injection were suppressive while CD25+ cells from 2 d post–LPs injection were not suppressive. Chicken non–Tregs appear, therefore, to up-regulate CD25 transiently, with no suppressive properties, post–LPS treatment. The other possibility is Tregs undergoes extensive proliferation and lose suppressive properties post–LPS treatment. Because chicken Treg specific markers are not available, we cannot exclude either of the above possibility.

Compared to mammalian Tregs, research in avian Tregs are in earlier stages. Further characterization of avian Tregs will benefit poultry production. For example, avian Tregs, with anti–inflammatory potential, can be targeted to decrease inflammation and mortality during an immune response in commercial settings. In mammals, Treg–targeted therapy [anti–CTLA–4 , anti–IL–2 , anti–CD25 ] is applied for numerous situations, e.g. infections, tumors, autoimmune diseases, sepsis, shock, and vaccine. Similar to mammals, avian diseases will benefit from Treg–targeted therapy. A host immune response is a result of interplay between different components of the immune system. Interplay between Tregs and other components of the immune system will determine whether the outcome will be a persistent infection or successful pathogen clearance.

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