Regulatory T Cells in Arterivirus and Coronavirus Infections: Do They Protect Against Disease or Enhance it?

Abstract

Regulatory T cells (Tregs) are a subset of T cells that are responsible for maintaining peripheral immune tolerance and homeostasis. The hallmark of Tregs is the expression of the forkhead box P3 (FoxP3) transcription factor. Natural regulatory T cells (nTregs) are a distinct population of T cells that express CD4 and FoxP3. nTregs develop in the thymus and function in maintaining peripheral immune tolerance. Other CD4+, CD4-CD8-, and CD8+CD28- T cells can be induced to acquire regulatory function by antigenic stimulation, depending on the cytokine milieu. Inducible (or adaptive) Tregs frequently express high levels of the interleukin 2 receptor (CD25). Atypical Tregs express FoxP3 and CD4 but have no surface expression of CD25. Type 1 regulatory T cells (Tr1 cells) produce IL-10, while T helper 3 cells (Th3) produce TGF-β. The function of inducible Tregs is presumably to maintain immune homeostasis, especially in the context of chronic inflammation or infection. Induction of Tregs in coronaviral infections protects against the more severe forms of the disease attributable to the host response. However, arteriviruses have exploited these T cell subsets as a means to dampen the immune response allowing for viral persistence. Treg induction or activation in the pathogenesis of disease has been described in both porcine reproductive and respiratory syndrome virus, lactate dehydrogenase elevating virus, and mouse hepatitis virus. This review discusses the development and biology of regulatory T cells in the context of arteriviral and coronaviral infection.

Coronavirus infections and immune responses

“…MERS‐CoV and SARS‐CoV are β‐coronaviruses that can cause fatal lower respiratory tract infections and extrapulmonary manifestations 70–72 . T cells, CD4+ T cells, and CD8+ T cells particularly play a significant antiviral role by balancing the combat against pathogens and the risk of developing autoimmunity or overwhelming inflammation 73 . CD4+ T cells promote the production of virus‐specific antibodies by activating T‐dependent B cells.…”

Analysis of mRNA expression for genes associated with regulatory T lymphocytes (CD25, FoxP3, CTLA4, and IDO) after experimental infection with bovine viral diarrhea virus of low or high virulence in beef calves

“…Recent studies have demonstrated induction of Tregs during early phase of acute infection with PRRSV [16][17][18][19][20]. Moreover, the increased frequency of CD25 + FoxP3 + T cells during infection with PRRSV in pigs has been associated with an increased production of the inhibitory cytokines IL-10 and TGF-beta [18,20], lymphocyte suppression activity in vitro [20,32] and increased susceptibility to natural Mycoplasma hyopneumoniae infection [17]. The induction of this T cell subset could explain the decreased and delayed local [33][34][35] and systemic [6] PRRSV-directed cell mediated immunity in PRRS infection, and the generalized immunosuppression observed in acutely infected pigs.…”

A novel DNA vaccine for reduction of PRRSV-induced negative immunomodulatory effects: A proof of concept

“…Infection with Porcine reproductive and respiratory syndrome virus (PRRSV) usually induces slow and weak anti-viral immune responses, leading to persistent infection and immunosuppression [1][2][3][4][5]. The lack of anamnestic responses observed following PRRSV exposure in previously vaccinated pigs [6,7] implied that even the well-primed immune system was severely impaired during active PRRSV infection.…”

“…Interleukin-10 is essential for induction of PRRSV-specific Tregs [15]. The role of PRRSV-specific Tregs has also been linked to delayed induction of cellular responses and increased susceptibility of bacterial infection in infected hosts [5,16,17].…”