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

Abstract: Regulatory T cells (T_regs) are a subset of T cells that are responsible for maintaining peripheral immune tolerance and homeostasis. The hallmark of T_regs is the expression of the forkhead box P3 (FoxP3) transcription factor. Natural regulatory T cells (nT_regs) 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) T_regs frequently express high levels of the interleukin 2 receptor (CD25). Atypical T_regs 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 T_regs is presumably to maintain immune homeostasis, especially in the context of chronic inflammation or infection. Induction of T_regs 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. T_reg 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.