Influenza virus infection selectively triggers the accumulation and persistence of more potent Helios-expressing Foxp3⁺ regulatory T cells in the lungs

Foxp3⁺ regulatory T cells (Tregs) represent a special lineage of CD4⁺ T cells. Analysis of Treg response during primary and secondary influenza virus infection clearly demonstrates a robust accumulation of Tregs into the infected lungs and the existence of a population of long-lived antigen-specific memory Tregs in the same tissues after resolution of the infection. However, it remains unknown whether these Tregs co-express Helios, a member of the Ikaros transcription factor family. In this study, Foxp3⁺Helios⁺ and Foxp3⁺Helios^- Tregs in the lungs, mLNs and spleens of influenza virus-infected and uninfected control mice were tracked. The data show that while there is a co-existence of Foxp3⁺Helios⁺ and Foxp3⁺Helios^- Tregs in the tissues, the accumulated Tregs in the lungs and lung-draining mediastinal lymph nodes (mLNs) of the infected mice are highly enriched for Foxp3⁺Helios⁺ cells. It was further demonstrated that, after the clearance of primary infection, Foxp3⁺Helios⁺ cells have the ability to persist in the tissues over their Helios^- counterparts. More importantly, Foxp3⁺Helios⁺ Tregs accumulated in an accelerated kinetics during recall response to reinfection. In vitro analysis of Treg suppressive function revealed that Foxp3⁺Helios⁺ Tregs are more capable of suppressing influenza virus-specific CD8⁺ T cell activation, cytokine production and proliferation. Together, the data provide new insights into Treg responses during primary and secondary influenza virus infection and suggest that Foxp3⁺Helios⁺ Tregs predominantly drive the Treg responses.