Viral Antigen Induces Differentiation of Foxp3+ Natural Regulatory T Cells in Influenza Virus–Infected Mice

Abstract

We have examined the formation, participation and functional specialization of virus-reactive Foxp3+ regulatory T cells (Tregs) in a mouse model of influenza virus infection. “Natural” Tregs generated intra-thymically based on interactions with a self-peptide proliferated in response to a homologous viral antigen in the lungs, and to a lesser extent in the lung-draining mediastinal LN (medLN), of virus-infected mice. By contrast, conventional CD4+ T cells with identical TCR specificity underwent little or no conversion to become “adaptive” Tregs. The virus-reactive Tregs in the medLN and the lungs of infected mice upregulated a variety of molecules associated with Treg activation, and also acquired expression of molecules (T-bet, Blimp-1 and IL-10) that confer functional specialization to Tregs. Notably, however, the phenotypes of the T-bet+ Tregs obtained from these sites were distinct, since Tregs isolated from the lungs expressed significantly higher levels of T-bet, Blimp-1 and IL-10 than did Tregs from the medLN. Adoptive transfer of antigen-reactive Tregs led to decreased proliferation of anti-viral CD4+ and CD8+ effector T cells in the lungs of infected hosts, while depletion of Tregs had a reciprocal effect. These studies demonstrate that thymically-generated Tregs can become activated by a pathogen-derived peptide and acquire discrete T-bet+ Treg phenotypes while participating in and modulating an antiviral immune response.

PC61 (Anti-CD25) Treatment Inhibits Influenza A Virus-Expanded Regulatory T Cells and Severe Lung Pathology during a Subsequent Heterologous Lymphocytic Choriomeningitis Virus Infection

“…Recently, antigen-specific IAV-induced Treg cells have been reported to attenuate subsequent T cell responses and decrease pathology during a secondary challenge with heterosubtypic IAV infection (51,52). Here, we show for the first time that virusexpanded Treg cells could attenuate immune responses and influence induction of lung pathology during a subsequent unrelated nonpersistent virus infection.…”

Activation of the aryl hydrocarbon receptor during development enhances the pulmonary CD4+ T-cell response to viral infection

“…Their precise roles in the lung during infection are not yet fully understood, but they control the magnitude of immune responses to infectious and noninfectious agents in other tissues, suggesting they execute similar functions in the infected lung (2,5,11). Activation of the AHR in adult animals skews the differentiation pattern of these CD4 ϩ T-cell subsets by altering the ratio of conventional effector CD4 ϩ T cells to Tregs, thereby influencing immune mediated pathologies in nonpulmonary tissues (35).…”

Regulatory T Cells Resist Virus Infection-Induced Apoptosis

“…Treg cells play a critical role of regulating effector T cells, NK cells, neutrophils, monocytes, and macrophages early during viral infections, mitigating the pathology incurred by the immune response and prolonging survival of the infected mice (57)(58)(59)(60). The presence of virus-specific memory Treg cells can preserve lung function by limiting CD8 T cell response and reduc- ing pathology during homologous influenza rechallenge (61).…”