Role of regulatory T cells during virus infection

Abstract

The host response to viruses includes multiple cell types that have regulatory function. Most information focuses on CD4(+) regulatory T cells that express the transcription factor Foxp3(+) (Tregs), which are the topic of this review. We explain how viruses through specific and non-specific means can trigger the response of thymus-derived natural Tregs as well as induce Tregs. The latter derive under appropriate stimulation conditions either from uncommitted precursors or from differentiated cells that convert to become Tregs. We describe instances where Tregs appear to limit the efficacy of antiviral protective immunity and other, perhaps more common, immune-mediated inflammatory conditions, where the Tregs function to limit the extent of tissue damage that occurs during a virus infection. We discuss the controversial roles that Tregs may play in the pathogenesis of human immunodeficiency and hepatitis C virus infections. The issue of plasticity is discussed, as this may result in Tregs losing their protective function when present in inflammatory environments. Finally, we mention approaches used to manipulate Treg numbers and function and assess their current value and likely future success to manage the outcome of virus infection, especially those that are responsible for chronic tissue damage.

Keywords: immunopathology; infection; plasticity; regulatory T cells; therapy; virus.

Fig. 1. Possible pathways that viruses may use to induce/activate/expand Tregs as a mechanism to survive within the host

(A) Viruses can manipulate APCs by three different mechanisms: inducing anti-inflammatory cytokine production, modulating antigen presentation, or by interfering with co-stimulatory molecule expression. (B) Some viruses may have antigens that cross-react with self-antigens and will be recognized by the TCR on nTregs, or have antigens that are recognized by the TCR on naive Th0 cells that will become iTregs. iTregs can also recognize non-self antigens through their TCRs, which will induce them to proliferate Moreover, self-antigens released as a result of tissue damage could stimulate nTregs through their TCR. (C) Stimulation of TLRs expressed on Tregs by PAMPs from the virus, or DAMPs such as heat shock proteins, β-defensins, nucleic acid can directly induce regulatory T-cell activation. Stimulation independent of TCR can also happen by host-derived products such as cytokines released after infection (TGF-β, IL-2, IFN-γ, TNF-α), galectins (galectin-1 and galectin-9), cellular metabolites (like retinoic acid), and other molecules.