{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T16:44:04Z","timestamp":1768495444613,"version":"3.49.0"},"posted":{"date-parts":[[2021,3,25]]},"group-title":"Immunology","reference-count":62,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2021,3,25]],"date-time":"2021-03-25T00:00:00Z","timestamp":1616630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2021,3,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Elicitation of lung tissue-resident memory CD8 T cells (T\n                  <jats:sub>RM<\/jats:sub>\n                  s) is a goal of T-cell based vaccines against respiratory viral pathogens such as influenza A virus (IAV). Chemokine receptor 2 (CCR2)-dependent monocyte trafficking plays an essential role in the establishment of CD8 T\n                  <jats:sub>RM<\/jats:sub>\n                  s in lungs of IAV-infected mice. Here, we used a combination adjuvant-based subunit vaccine strategy that evokes multifaceted (T\n                  <jats:sub>C<\/jats:sub>\n                  1\/T\n                  <jats:sub>C<\/jats:sub>\n                  17\/T\n                  <jats:sub>H<\/jats:sub>\n                  1\/T\n                  <jats:sub>H<\/jats:sub>\n                  17) IAV nucleoprotein-specific lung T\n                  <jats:sub>RM<\/jats:sub>\n                  s, to determine whether CCR2 and monocyte infiltration are essential for vaccine-induced T\n                  <jats:sub>RM<\/jats:sub>\n                  development and protective immunity to IAV in lungs. Following intranasal vaccination, neutrophils, monocytes, conventional dendrtitic cells (DCs) and monocyte-derived DCs internalized and processed vaccine antigen in lungs. We also found that Basic Leucine Zipper ATF-Like Transcription Factor 3 (BATF-3)-dependent DCs were essential for eliciting T cell responses, but CCR2 deficiency enhanced the differentiation of CD127\n                  <jats:sup>HI<\/jats:sup>\n                  \/KLRG-1\n                  <jats:sup>LO<\/jats:sup>\n                  , OX40\n                  <jats:sup>+ve<\/jats:sup>\n                  CD62L\n                  <jats:sup>+ve<\/jats:sup>\n                  and mucosally imprinted CD69\n                  <jats:sup>+ve<\/jats:sup>\n                  CD103\n                  <jats:sup>+ve<\/jats:sup>\n                  effector and memory CD8 T cells in lungs and airways of vaccinated mice. Mechanistically, increased development of lung T\n                  <jats:sub>RM<\/jats:sub>\n                  s, induced by CCR2 deficiency was linked to dampened expression of T-bet, but not altered TCF-1 levels or T cell receptor signaling in CD8 T cells. T1\/T17 functional programming, parenchymal localization of CD8\/CD4 effector and memory T cells, recall T cell responses and protective immunity to a lethal IAV infection were unaffected in CCR2-deficient mice. Taken together, we identified a negative regulatory role for CCR2 and monocyte trafficking in mucosal imprinting and differentiation of vaccine-induced T\n                  <jats:sub>RM<\/jats:sub>\n                  s. Mechanistic insights from this study may aid the development of T-cell-based vaccines against respiratory viral pathogens including IAV and SARS-CoV-2.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Importance<\/jats:title>\n                  <jats:p>While antibody-based immunity to influenza A virus (IAV) is type and sub-type specific, lung and airway-resident memory T cells that recognize conserved epitopes in the internal viral proteins are known to provide heterosubtypic immunity. Hence, broadly protective IAV vaccines need to elicit robust T-cell memory in the respiratory tract. We have developed a combination adjuvant-based IAV nucleoprotein vaccine that elicits strong CD4 and CD8 T cell memory in lungs and protects against H1N1 and H5N1 strains of IAV. In this study, we examined the mechanisms that control vaccine-induced protective memory T cells in the respiratory tract. We found that trafficking of monocytes into lungs might limit the development of anti-viral lung-resident memory T cells, following intranasal vaccination. These findings suggested that strategies that limit monocyte infiltration can potentiate vaccine-induced frontline T-cell immunity to respiratory viruses such as IAV and SARS-CoV-2.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2021.03.24.436901","type":"posted-content","created":{"date-parts":[[2021,3,25]],"date-time":"2021-03-25T17:56:20Z","timestamp":1616694980000},"source":"Crossref","is-referenced-by-count":0,"title":["CCR2 Regulates Vaccine-Induced Mucosal T-Cell Memory to Influenza A Virus"],"prefix":"10.64898","author":[{"given":"Woojong","family":"Lee","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brock","family":"Kingstad-Bakke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ross M.","family":"Kedl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5061-8296","authenticated-orcid":false,"given":"Yoshihiro","family":"Kawaoka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1794-3358","authenticated-orcid":false,"given":"M.","family":"Suresh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024080517174350000_2021.03.24.436901v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/32588"},{"key":"2024080517174350000_2021.03.24.436901v1.2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.167.2.741"},{"key":"2024080517174350000_2021.03.24.436901v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2005.05.015"},{"key":"2024080517174350000_2021.03.24.436901v1.4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0004204"},{"key":"2024080517174350000_2021.03.24.436901v1.5","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0902022"},{"key":"2024080517174350000_2021.03.24.436901v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3224"},{"key":"2024080517174350000_2021.03.24.436901v1.7","doi-asserted-by":"crossref","unstructured":"Pizzolla A , Nguyen THO , Smith JM , Brooks AG , Kedzieska K , Heath WR , Reading PC , Wakim LM . 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