Regulatory T Cells Prevent Th2 Immune Responses and Pulmonary Eosinophilia during Respiratory Syncytial Virus Infection in Mice

Abstract

During viral infection, inflammation and recovery are tightly controlled by competing proinflammatory and regulatory immune pathways. Respiratory syncytial virus (RSV) is the leading global cause of infantile bronchiolitis, which is associated with recurrent wheeze and asthma diagnosis in later life. Th2-driven disease has been well described under some conditions for RSV-infected mice. In the present studies, we used the Foxp3DTR mice (which allow specific conditional depletion of Foxp3+ T cells) to investigate the functional effects of regulatory T cells (Tregs) during A2-strain RSV infection. Infected Treg-depleted mice lost significantly more weight than wild-type mice, indicating enhanced disease. This enhancement was characterized by increased cellularity in the bronchoalveolar lavage (BAL) fluid and notable lung eosinophilia not seen in control mice. This was accompanied by abundant CD4+ and CD8+ T cells exhibiting an activated phenotype and induction of interleukin 13 (IL-13)- and GATA3-expressing Th2-type CD4+ T cells that remained present in the airways even 14 days after infection. Therefore, Treg cells perform vital anti-inflammatory functions during RSV infection, suppressing pathogenic T cell responses and inhibiting lung eosinophilia. These findings provide additional evidence that dysregulation of normal immune responses to viral infection may contribute to severe RSV disease.

The role of Th17 and Treg responses in the pathogenesis of RSV infection

“…The Treg and Th17 subsets have distinct and opposing features in this context, as demonstrated by their effects on viral clearance, clinical severity, and Th2-oriented immune response (see Table 1). Specifically, the Treg immune response will ensure an efficient viral clearance and inhibition of the Th2-oriented immune response resulting in a less severe clinical picture (34,(36)(37)(38)(39). Although evidence is less conclusive than is the case for the Treg immune response, the Th17 immune response is thought to hamper an efficient viral clearance and further enhance a Th2 immune response resulting in a more severe clinical picture (50).…”

“…Combined with an observed splenomegaly due to proliferation of CD4 + and CD8 + T-cells, this suggests a systemic inflammatory response and an excessive RSV-specific T-cell response in Treg-depleted mice. In this setting, the abundant presence of CD8 + T-cells may surpass their contribution to effective viral clearance and may lead to tissue pathology and an increased disease severity, due to an increased, unrestrained production of TNF-α and IFN-γ by the CD8 + T-cells (34,39).…”

“…Thirdly, spontaneously developing Th2-type pathologies were described in Treg-depleted mice as Treg cells not only control the immunological environment in order to avoid excessive inflammatory T-cell responses, but also aid to limit inefficient Th2-type immune responses (39). In contrast to depleting Treg cells, stimulating the Treg cells in function and numbers by using IL-2/anti-IL-2 immune complexes limits lung inflammation and disease severity without preventing viral clearance (38).…”

Prophylaxis with a Respiratory Syncytial Virus (RSV) Anti-G Protein Monoclonal Antibody Shifts the Adaptive Immune Response to RSV rA2-line19F Infection from Th2 to Th1 in BALB/c Mice

“…Next, we studied the regulatory T cells (Tregs), which are associated with controlling the immune-response and avoiding autoimmune-and immune response-induced disease (55,56). During RSV infection, Treg cells limit antigen-specific T cell responses, suppress inflammation, and may help to control viral replication (57)(58)(59)(60). Our results show that prophylaxis with MAb 131-2G slightly (P Յ 0.05) increased the percentages of FoxP3 ϩ and Foxp3 ϩ IL-10 ϩ CD4 T cells compared to untreated r19F-infected mice (Fig.…”

A Recombinant G Protein Plus Cyclosporine A–Based Respiratory Syncytial Virus Vaccine Elicits Humoral and Regulatory T Cell Responses against Infection without Vaccine-Enhanced Disease

“…Recently, a study demonstrated that within the harmful Th2 response elicited in the lung by infection after FI-RSV vaccination there was a low content of the Treg cells that are needed to attenuate such inflammation and tissue damage (33). The Treg subtype of CD4 + Th cells (34) uses a number of mechanisms for homeostatic control of overexuberant or incorrect immune responses.…”