PD-1 and ICOS counter-regulate tissue resident regulatory T cell development and IL-10 production during flu

Regulatory T cells that express the transcription factor Foxp3 (Treg cells) are a highly heterogenous population of immunoregulatory cells critical for maintaining immune homeostasis and preventing immunopathology during infections. Tissue resident Treg (TR-Treg) cells are maintained within nonlymphoid tissues and have been shown to suppress proinflammatory tissue resident T cell responses and promote tissue repair. Human populations are repetitively exposed to influenza infections and lung tissue resident effector T cell responses are associated with flu-induced long-term pulmonary sequelae. The kinetics of TR-Treg cell development and molecular features of TR-Treg cells during repeated and/or long-term flu infections are unclear. Utilizing a Foxp3(RFP)/IL-10(GFP) dual reporter mouse model along with intravascular fluorescent in vivo labeling, we characterized the TR-Treg cell responses to repetitive heterosubtypic influenza infections. We found lung tissue resident Treg cells accumulated and expressed high levels of co-inhibitory and co-stimulatory receptors post primary and secondary infections. Blockade of PD-1 or ICOS signaling reveals that PD-1 and ICOS signaling pathways counter-regulate TR-Treg cell expansion and IL-10 production, during secondary influenza infection. Furthermore, the virus-specific TR-Treg cell response displayed distinct kinetics, when compared to conventional CD4(+) tissue resident memory T cells, during secondary flu infection. Our results provide insight into the tissue resident Foxp3(+) regulatory T cell response during repetitive flu infections, which may be applicable to other respiratory infectious diseases such as tuberculosis and COVID.

Automated summary

This study characterized the development and molecular features of tissue resident regulatory T cells (TR-Treg cells) during repetitive heterosubtypic influenza infections. The results showed that lung tissue resident Treg cells accumulated and expressed high levels of co-inhibitory and co-stimulatory receptors after primary and secondary infections. The PD-1 and ICOS signaling pathways counter-regulated the expansion and IL-10 production of TR-Treg cells during secondary influenza infection. Furthermore, the virus-specific TR-Treg cell response displayed distinct kinetics compared to conventional CD4(+) tissue resident memory T cells during secondary flu infection.