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Immunol."],"abstract":"<jats:p>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<jats:sup>RFP<\/jats:sup>\/IL-10<jats:sup>GFP<\/jats:sup>dual reporter mouse model along with intravascular fluorescent<jats:italic>in vivo<\/jats:italic>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<jats:sup>+<\/jats:sup>tissue resident memory T cells, during secondary flu infection. Our results provide insight into the tissue resident Foxp3<jats:sup>+<\/jats:sup>regulatory T cell response during repetitive flu infections, which may be applicable to other respiratory infectious diseases such as tuberculosis and COVID.<\/jats:p>","DOI":"10.3389\/fimmu.2022.984476","type":"journal-article","created":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T05:59:11Z","timestamp":1662616751000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["PD-1 and ICOS counter-regulate tissue resident regulatory T cell development and IL-10 production during flu"],"prefix":"10.3389","volume":"13","author":[{"given":"Michael C.","family":"McGee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Magazine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rezwanul","family":"Islam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariano","family":"Carossino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weishan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2012.00051","article-title":"Molecular mechanisms of treg-mediated T cell suppression","volume":"3","author":"Schmidt","year":"2012","journal-title":"Front Immunol"},{"key":"B2","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.155.3.1151","article-title":"Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). 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