{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T14:54:07Z","timestamp":1790952847424,"version":"4.1.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T00:00:00Z","timestamp":1638403200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The requirement for vaccine-induced tissue-resident immunity for protection against one or repeated infections with <jats:italic>Chlamydia trachomatis (C.t.)<\/jats:italic> is still not fully resolved. In this study, our aim was to investigate to which degree tissue-resident Th1\/Th17 T cells in the genital tract (GT) could add to the protection mediated by circulating immunity. Out of several mucosal vaccine strategies, a strategy termed SIM (for simultaneous intrauterine and parenteral immunization with CAF01 adjuvanted CTH522), was superior in generating genital tract tissue-resident Th1\/Th17 T cell immunity. This led to a faster and stronger local CD4 T cell response post infection, consisting of multifunctional IFN\u03b3\/TNF\u03b1-producing Th1 T cells and IFN\u03b3\/TNF\u03b1\/IL-17-producing Th17 T cells, and a faster recruitment of innate immune cells. Post infection, SIM animals showed an additional significant reduction in bacterial levels compared to mice having received only a parenteral vaccine. Nevertheless, the parenteral strategy reduced bacterial levels by 75%, and interestingly, post infection, these mice generated their own vaccine-derived genital tract tissue-resident memory Th1\/Th17 T cells, which upon a subsequent infection showed as fast an activation in the genital tract, as observed in SIM mice. Furthermore, in contrast to after the first infection, both groups of mice now showed a similar infection-induced boost in local vaginal IgA and IgG titers. Thus, vaccine-induced resident immunity, generated pre-infection, led to an advantage in the response against the first infection, but not the second infection, suggesting that a parenteral vaccine strategy is a suitable vaccine strategy against infections with <jats:italic>Chlamydia trachomatis<\/jats:italic>.<\/jats:p>","DOI":"10.3389\/fimmu.2021.790463","type":"journal-article","created":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T06:14:18Z","timestamp":1638425658000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":24,"title":["Th1\/Th17 T cell Tissue-Resident Immunity Increases Protection, But Is Not Required in a Vaccine Strategy Against Genital Infection With Chlamydia trachomatis"],"prefix":"10.3389","volume":"12","author":[{"given":"Nina Dieu Nhien Tran","family":"Nguyen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Safia","family":"Guleed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja Weinreich","family":"Olsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Follmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan Pravsgaard","family":"Christensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes","family":"Dietrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,2]]},"reference":[{"key":"B1","volume-title":"Report on Global Sexually Transmitted Infection Surveillance","year":"2018"},{"key":"B2","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1097\/AOG.0b013e31825a6bc9","article-title":"Subclinical Pelvic Inflammatory Disease and Infertility","volume":"120","author":"Wiesenfeld","year":"2012","journal-title":"Obstet Gynecol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/0028-2243(94)90048-5","article-title":"Laparoscopic Study on the Microbiology and Severity of Acute Pelvic Inflammatory Disease","volume":"57","author":"Heinonen","year":"1994","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1097\/00007435-199207000-00001","article-title":"Pelvic Inflammatory Disease and Fertility. A Cohort Study of 1,844 Women With Laparoscopically Verified Disease and 657 Control Women With Normal Laparoscopic Results","volume":"19","author":"Westrom","year":"1992","journal-title":"Sex Transm Dis"},{"key":"B5","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1086\/648734","article-title":"Repeated Chlamydia Trachomatis Genital Infections in Adolescent Women","volume":"201","author":"Batteiger","year":"2010","journal-title":"J Infect Dis"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00331","article-title":"Mucosal Resident Memory CD4 T Cells in Protection and Immunopathology","volume":"5","author":"Turner","year":"2014","journal-title":"Front Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1126\/science.1257530","article-title":"T Cell Memory. A Local Macrophage Chemokine Network Sustains Protective Tissue-Resident Memory CD4 T Cells","volume":"346","author":"Iijima","year":"2014","journal-title":"Sci"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa8205","article-title":"VACCINES. A Mucosal Vaccine Against Chlamydia Trachomatis Generates Two Waves of Protective Memory T Cells","volume":"348","author":"Stary","year":"2015","journal-title":"Science"},{"key":"B9","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1126\/science.1254536","article-title":"Resident Memory CD8 T Cells Trigger Protective Innate and Adaptive Immune Responses","volume":"346","author":"Schenkel","year":"2014","journal-title":"Science"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20181365","article-title":"CD4(+) Resident Memory T Cells Dominate Immunosurveillance and Orchestrate Local Recall Responses","volume":"216","author":"Beura","year":"2019","journal-title":"J Exp Med"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.1016\/j.cell.2019.07.032","article-title":"Effector T(H)17 Cells Give Rise to Long-Lived T(RM) Cells That Are Essential for an Immediate Response Against Bacterial Infection","volume":"178","author":"Amezcua Vesely","year":"2019","journal-title":"Cell"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006349","article-title":"Skin-Resident CD4+ T Cells Protect Against Leishmania Major by Recruiting and Activating Inflammatory Monocytes","volume":"13","author":"Glennie","year":"2017","journal-title":"PloS Pathog"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2568","article-title":"Sensing and Alarm Function of Resident Memory CD8\u207a T Cells","volume":"14","author":"Schenkel","year":"2013","journal-title":"Nat Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/nature11522","article-title":"A Vaccine Strategy That Protects Against Genital Herpes by Establishing Local Memory T Cells","volume":"491","author":"Shin","year":"2012","journal-title":"Nature"},{"key":"B15","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/s41541-020-0157-x","article-title":"Parenteral Vaccination Protects Against Transcervical Infection With Chlamydia Trachomatis and Generate Tissue-Resident T Cells Post-Challenge","volume":"5","author":"Nguyen","year":"2020","journal-title":"NPJ Vaccines"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00569","article-title":"Simultaneous Subcutaneous and Intranasal Administration of a CAF01-Adjuvanted Chlamydia Vaccine Elicits Elevated IgA and Protective Th1\/Th17 Responses in the Genital Tract","volume":"8","author":"Wern","year":"2017","journal-title":"Front Immunol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"jiv137","DOI":"10.1093\/infdis\/jiv137","article-title":"Protection Against Chlamydia Trachomatis Infection and Upper Genital Tract Pathological Changes by Vaccine-Promoted Neutralizing Antibodies Directed to the VD4 of the Major Outer Membrane Protein","volume":"212","author":"Olsen","year":"2015","journal-title":"J Infect Dis"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1128\/iai.06338-11","article-title":"Chlamydia Muridarum T Cell Antigens and Adjuvants That Induce Protective Immunity in Mice","volume":"80","author":"Yu","year":"2012","journal-title":"Infect Immun"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1086\/508203","article-title":"Identification of CT521 as a Frequent Target of Th1 Cells in Patients With Urogenital Chlamydia Trachomatis Infection","volume":"194","author":"Olsen","year":"2006","journal-title":"J Infect Dis"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2016.28","article-title":"Vaccine-Induced Th17 Cells Are Established as Resident Memory Cells in the Lung and Promote Local IgA Responses [Article]","volume":"10","author":"Christensen","year":"2016","journal-title":"Mucosal Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2014.005","article-title":"Intravascular Staining for Discrimination of Vascular and Tissue Leukocytes","volume":"9","author":"Anderson","year":"2014","journal-title":"Nat Protoc"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/nm1592","article-title":"Multifunctional TH1 Cells Define a Correlate of Vaccine-Mediated Protection Against Leishmania Major","volume":"13","author":"Darrah","year":"2007","journal-title":"Nat Med"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1086\/314806","article-title":"Mucosal Immune System of the Human Genital Tract","volume":"179","author":"Mestecky","year":"1999","journal-title":"J Infect Dis"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1103183","article-title":"Synchronization of Dendritic Cell Activation and Antigen Exposure is Required for the Induction of Th1\/Th17 Responses","volume":"188","author":"Kamath","year":"2012","journal-title":"J Immunol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"55","DOI":"10.4236\/wjv.2020.104005","article-title":"A Novel LNP-Based Chlamydia Subunit Vaccine Formulation That Induces Th1 Responses Without Upregulating IL-17 Provides Equivalent Protection in Mice as Formulations That Induced IL-17 and Th1 Cytokines","volume":"10","author":"Boddicker","year":"2020","journal-title":"World J Vaccines"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01374-09","article-title":"Chlamydia Muridarum T-Cell Antigens Formulated With the Adjuvant DDA\/TDB Induce Immunity Against Infection That Correlates With a High Frequency of Gamma Interferon (IFN-Gamma)\/Tumor Necrosis Factor Alpha and IFN-Gamma\/Interleukin-17 Double-Positive CD4+ T Cells","volume":"78","author":"Yu","year":"2020","journal-title":"Infect Immun"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1700914","article-title":"A Chlamydia-Specific TCR-Transgenic Mouse Demonstrates Th1 Polyfunctionality With Enhanced Effector Function","volume":"199","author":"Poston","year":"2017","journal-title":"J Immunol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/imm.13280","article-title":"Cytokine-Regulated Th17 Plasticity in Human Health and Diseases","volume":"163","author":"Cerboni","year":"2021","journal-title":"Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1600737","article-title":"Ex-Th17 (Nonclassical Th1) Cells Are Functionally Distinct From Classical Th1 and Th17 Cells and Are Not Constrained by Regulatory T Cells","volume":"198","author":"Basdeo","year":"2017","journal-title":"J Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00984-10","article-title":"Interleukin-17 Contributes to Generation of Th1 Immunity and Neutrophil Recruitment During Chlamydia Muridarum Genital Tract Infection But Is Not Required for Macrophage Influx or Normal Resolution of Infection [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov\u2019t]","volume":"79","author":"Scurlock","year":"2011","journal-title":"Infect Immun"},{"key":"B31","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1038\/s41541-020-00239-7","article-title":"Vaccination With the Recombinant Major Outer Membrane Protein Elicits Long-Term Protection in Mice Against Vaginal Shedding and Infertility Following a Chlamydia Muridarum Genital Challenge","volume":"5","author":"Pal","year":"2020","journal-title":"NPJ Vaccines"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00628","article-title":"Intramuscular Priming and Intranasal Boosting Induce Strong Genital Immunity Through Secretory Iga in Minipigs Infected With Chlamydia Trachomatis","volume":"6","author":"Lorenzen","year":"2015","journal-title":"Front Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2011.05.013","article-title":"Induction of Protection Against Vaginal Shedding and Infertility by a Recombinant Chlamydia Vaccine [Research Support, N.I.H., Extramural]","volume":"29","author":"Carmichael","year":"2011","journal-title":"Vaccine"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0006999","article-title":"Transient Facial Nerve Paralysis (Bell\u2019s Palsy) Following Intranasal Delivery of a Genetically Detoxified Mutant of Escherichia Coli Heat Labile Toxin","volume":"4","author":"Lewis","year":"2009","journal-title":"PloS One"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2016.06.081","article-title":"Recombinant Polymorphic Membrane Protein D in Combination With a Novel, Second-Generation Lipid Adjuvant Protects Against Intra-Vaginal Chlamydia Trachomatis Infection in Mice","volume":"34","author":"Paes","year":"2016","journal-title":"Vaccine"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(19)30279-8","article-title":"Safety and Immunogenicity of the Chlamydia Vaccine Candidate CTH522 Adjuvanted With CAF01 Liposomes or Aluminium Hydroxide: A First-in-Human, Randomised, Double-Blind, Placebo-Controlled, Phase 1 Trial","volume":"19","author":"Abraham","year":"2019","journal-title":"Lancet Infect Dis"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2104407118","article-title":"Circulating Immunity Protects the Female Reproductive Tract From Chlamydia Infection","volume":"118","author":"Labuda","year":"2021","journal-title":"Proc Natl Acad Sci USA"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.790463\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T06:14:21Z","timestamp":1638425661000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.790463\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,2]]},"references-count":37,"alternative-id":["10.3389\/fimmu.2021.790463"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.790463","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,2]]},"article-number":"790463"}}