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Immunol."],"abstract":"<jats:p>Memory T cells are crucial for both local and systemic protection against pathogens over a long period of time. Three major subsets of memory T cells; effector memory T (T<jats:sub>EM<\/jats:sub>) cells, central memory T (T<jats:sub>CM<\/jats:sub>) cells, and tissue-resident memory T (T<jats:sub>RM<\/jats:sub>) cells have been identified. The most recently identified subset, T<jats:sub>RM<\/jats:sub> cells, is characterized by the expression of the C-type lectin CD69 and\/or the integrin CD103. T<jats:sub>RM<\/jats:sub> cells persist locally at sites of mucosal tissue, such as the lung, where they provide frontline defense against various pathogens. Importantly, however, T<jats:sub>RM<\/jats:sub> cells are also involved in shaping the pathology of inflammatory diseases. A number of pioneering studies revealed important roles of CD8<jats:sup>+<\/jats:sup> T<jats:sub>RM<\/jats:sub> cells, particularly those in the local control of viral infection. However, the protective function and pathogenic role of CD4<jats:sup>+<\/jats:sup> T<jats:sub>RM<\/jats:sub> cells that reside within the mucosal tissue remain largely unknown. In this review, we discuss the ambivalent feature of CD4<jats:sup>+<\/jats:sup> T<jats:sub>RM<\/jats:sub> cells in the protective and pathological immune responses. We also review the transcriptional and epigenetic characteristics of CD4<jats:sup>+<\/jats:sup> T<jats:sub>RM<\/jats:sub> cells in the lung that have been elucidated by recent technical approaches. A better understanding of the function of CD4<jats:sup>+<\/jats:sup> T<jats:sub>RM<\/jats:sub> cells is crucial for the development of both effective vaccination against pathogens and new therapeutic strategies for intractable inflammatory diseases, such as inflammatory bowel diseases and chronic allergic diseases.<\/jats:p>","DOI":"10.3389\/fimmu.2021.616309","type":"journal-article","created":{"date-parts":[[2021,4,21]],"date-time":"2021-04-21T19:01:51Z","timestamp":1619031711000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":50,"title":["The Role of CD4+ Resident Memory T Cells in Local Immunity in the Mucosal Tissue \u2013 Protection Versus Pathology \u2013"],"prefix":"10.3389","volume":"12","author":[{"given":"Kiyoshi","family":"Hirahara","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kota","family":"Kokubo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ami","family":"Aoki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Kiuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshinori","family":"Nakayama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2004.09.012","article-title":"Chemoattractants and their receptors in homeostasis and inflammation","volume":"16","author":"Sallusto","year":"2004","journal-title":"Curr Opin Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/44385","article-title":"Two subsets of memory T lymphocytes with distinct homing potentials and effector functions","volume":"401","author":"Sallusto","year":"1999","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1084\/jem.194.12.1711","article-title":"Cytokine-driven proliferation and differentiation of human naive, central memory, and effector memory CD4(+) T cells","volume":"194","author":"Geginat","year":"2001","journal-title":"J Exp Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.12.8299","article-title":"The central memory CD4+ T cell population generated during Leishmania major infection requires IL-12 to produce IFN-gamma","volume":"180","author":"Pakpour","year":"2008","journal-title":"J Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1084\/jem.186.9.1407","article-title":"Phenotypic and functional separation of memory and effector human CD8+ T cells","volume":"186","author":"Hamann","year":"1997","journal-title":"J Exp Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/ni1009","article-title":"Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells","volume":"4","author":"Kaech","year":"2003","journal-title":"Nat Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20070322","article-title":"Activation phenotype, rather than central- or effector-memory phenotype, predicts the recall efficacy of memory CD8+ T cells","volume":"204","author":"Hikono","year":"2007","journal-title":"J Exp Med"},{"key":"B8","doi-asserted-by":"publisher","first-page":"8306","DOI":"10.1038\/ncomms9306","article-title":"Functional classification of memory CD8(+) T cells by CX3CR1 expression","volume":"6","author":"Bottcher","year":"2015","journal-title":"Nat Commun"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.10.018","article-title":"The Chemokine Receptor CX3CR1 Defines Three Antigen-Experienced CD8 T Cell Subsets with Distinct Roles in Immune Surveillance and Homeostasis","volume":"45","author":"Gerlach","year":"2016","journal-title":"Immunity"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-042617-053214","article-title":"Tissue-Resident T Cells and Other Resident Leukocytes","volume":"37","author":"Masopust","year":"2019","journal-title":"Annu Rev Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1102243","article-title":"Cutting edge: Tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection","volume":"187","author":"Teijaro","year":"2011","journal-title":"J Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2568","article-title":"Sensing and alarm function of resident memory CD8(+) T cells","volume":"14","author":"Schenkel","year":"2013","journal-title":"Nat Immunol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1126\/science.1254536","article-title":"T cell memory. 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