{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T11:43:06Z","timestamp":1767008586658,"version":"3.41.2"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T00:00:00Z","timestamp":1680220800000},"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:sec><jats:title>Introduction<\/jats:title><jats:p>C-type lectin receptor (CLR) agonists emerged as superior inducers of primary B cell responses in early life compared with Toll-like receptor (TLR) agonists, while both types of adjuvants are potent in adults.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, we explored the mechanisms accounting for the differences in neonatal adjuvanticity between a CLR-based (CAF<jats:sup>\u00ae<\/jats:sup>01) and a TLR4-based (GLA-SE) adjuvant administered with influenza hemagglutinin (HA) in neonatal mice, by using transcriptomics and systems biology analyses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>On day 7 after immunization, HA\/CAF01 increased IL6 and IL21 levels in the draining lymph nodes, while HA\/GLA-SE increased IL10. CAF01 induced mixed Th1\/Th17 neonatal responses while T cell responses induced by GLA-SE had a more pronounced Th2-profile. Only CAF01 induced T follicular helper (Tfh) cells expressing high levels of IL21 similar to levels induced in adult mice, which is essential for germinal center (GC) formation. Accordingly, only CAF01- induced neonatal Tfh cells activated adoptively transferred hen egg lysozyme (HEL)-specific B cells to form HEL<jats:sup>+<\/jats:sup> GC B cells in neonatal mice upon vaccination with HEL-OVA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Collectively, the data show that CLR-based adjuvants are promising neonatal and infant adjuvants due to their ability to harness Tfh responses in early life.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1155200","type":"journal-article","created":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T08:54:50Z","timestamp":1680252890000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["C-type lectin receptor agonists elicit functional IL21-expressing Tfh cells and induce primary B cell responses in neonates"],"prefix":"10.3389","volume":"14","author":[{"given":"Maria","family":"Vono","sequence":"first","affiliation":[]},{"given":"Beatris","family":"Mastelic-Gavillet","sequence":"additional","affiliation":[]},{"given":"Elodie","family":"Mohr","sequence":"additional","affiliation":[]},{"given":"Malin","family":"\u00d6stensson","sequence":"additional","affiliation":[]},{"given":"Josefine","family":"Persson","sequence":"additional","affiliation":[]},{"given":"Thorunn A.","family":"Olafsdottir","sequence":"additional","affiliation":[]},{"given":"Sylvain","family":"Lemeille","sequence":"additional","affiliation":[]},{"given":"David","family":"Pejoski","sequence":"additional","affiliation":[]},{"given":"Oliver","family":"Hartley","sequence":"additional","affiliation":[]},{"given":"Dennis","family":"Christensen","sequence":"additional","affiliation":[]},{"given":"Peter","family":"Andersen","sequence":"additional","affiliation":[]},{"given":"Arnaud M.","family":"Didierlaurent","sequence":"additional","affiliation":[]},{"given":"Ali M.","family":"Harandi","sequence":"additional","affiliation":[]},{"given":"Paul-Henri","family":"Lambert","sequence":"additional","affiliation":[]},{"given":"Claire-Anne","family":"Siegrist","sequence":"additional","affiliation":[]}],"member":"1965","published-online":{"date-parts":[[2023,3,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2020.00005","article-title":"Advantages and limitations of the neonatal immune system","volume":"8","author":"Tsafaras","year":"2020","journal-title":"Front Pediatr"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.2002.01817.x","article-title":"Neonatal dendritic cells are intrinsically biased against Th-1 immune responses","volume":"128","author":"Langrish","year":"2002","journal-title":"Clin Exp Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.7.4312","article-title":"Regulatory activity of autocrine IL-10 on dendritic cell functions","volume":"166","author":"Corinti","year":"2001","journal-title":"J Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.6.2824","article-title":"Unresponsiveness to lymphoid-mediated signals at the neonatal follicular dendritic cell precursor level contributes to delayed germinal center induction and limitations of neonatal antibody responses to T-dependent antigens","volume":"170","author":"Pihlgren","year":"2003","journal-title":"J Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1201143","article-title":"Environmental and T cell-intrinsic factors limit the expansion of neonatal follicular T helper cells but may be circumvented by specific adjuvants","volume":"189","author":"Mastelic","year":"2012","journal-title":"J Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1203288","article-title":"Neonatal follicular Th cell responses are impaired and modulated by IL-4","volume":"191","author":"Debock","year":"2013","journal-title":"J Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1586\/1744666X.2014.942288","article-title":"Immune responses in neonates","volume":"10","author":"Basha","year":"2014","journal-title":"Expert Rev Clin Immunol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"90ps27","DOI":"10.1126\/scitranslmed.3001880","article-title":"Development of newborn and infant vaccines","volume":"3","author":"Sanchez-Schmitz","year":"2011","journal-title":"Sci Transl Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0007302","article-title":"Randomized controlled trial of RTS,S\/AS02D and RTS,S\/AS01E malaria candidate vaccines given according to different schedules in ghanaian children","volume":"4","author":"Owusu-Agyei","year":"2009","journal-title":"PloS One"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01760","article-title":"AS03- and MF59-adjuvanted influenza vaccines in children","volume":"8","author":"Wilkins","year":"2017","journal-title":"Front Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1402071","article-title":"MF59 mediates its b cell adjuvanticity by promoting T follicular helper cells and thus germinal center responses in adult and early life","volume":"194","author":"Mastelic Gavillet","year":"2015","journal-title":"J Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1080\/1744666X.2019.1642748","article-title":"Neonatal vaccine effectiveness and the role of adjuvants","volume":"15","author":"Sakala","year":"2019","journal-title":"Expert Rev Clin Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00381","article-title":"Overcoming the neonatal limitations of inducing germinal centers through liposome-based adjuvants including c-type lectin agonists trehalose dibehenate or curdlan","volume":"9","author":"Vono","year":"2018","journal-title":"Front Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0901481","article-title":"Neonatal innate TLR-mediated responses are distinct from those of adults","volume":"183","author":"Kollmann","year":"2009","journal-title":"J Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.7.4627","article-title":"Selective impairment of TLR-mediated innate immunity in human newborns: neonatal blood plasma reduces monocyte TNF-alpha induction by bacterial lipopeptides, lipopolysaccharide, and imiquimod, but preserves the response to r-848","volume":"173","author":"Levy","year":"2004","journal-title":"J Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0018185","article-title":"Age-dependent maturation of toll-like receptor-mediated cytokine responses in Gambian infants","volume":"6","author":"Burl","year":"2011","journal-title":"PloS One"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0016333","article-title":"Development and characterization of synthetic glucopyranosyl lipid adjuvant system as a vaccine adjuvant","volume":"6","author":"Coler","year":"2011","journal-title":"PloS One"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2013.08.064","article-title":"Evaluation of safety and immunogenicity of recombinant influenza hemagglutinin (H5\/Indonesia\/05\/2005) formulated with and without a stable oil-in-water emulsion containing glucopyranosyl-lipid a (SE+GLA) adjuvant","volume":"31","author":"Treanor","year":"2013","journal-title":"Vaccine"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2006.03.071","article-title":"IC31, a novel adjuvant signaling via TLR9, induces potent cellular and humoral immune responses","volume":"24","author":"Schellack","year":"2006","journal-title":"Vaccine"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1600282","article-title":"Age-specific adjuvant synergy: Dual TLR7\/8 and mincle activation of human newborn dendritic cells enables thl polarization","volume":"197","author":"van Haren","year":"2016","journal-title":"J Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0005771","article-title":"And neonatal multifunctional T cells through the exquisite targeting of dendritic cells","volume":"4","author":"Kamath","year":"2009","journal-title":"PloS One 4"},{"key":"B22","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1080\/08982100902726820","article-title":"Liposome-based cationic adjuvant formulations (CAF): Past, present, and future","volume":"19","author":"Christensen","year":"2009","journal-title":"J Liposome Res"},{"key":"B23","doi-asserted-by":"publisher","first-page":"39097","DOI":"10.1038\/srep39097","article-title":"Comparative systems analyses reveal molecular signatures of clinically tested vaccine adjuvants","volume":"6","author":"Olafsdottir","year":"2016","journal-title":"Sci Rep"},{"key":"B24","doi-asserted-by":"publisher","first-page":"19570","DOI":"10.1038\/srep19570","article-title":"Different human vaccine adjuvants promote distinct antigen-independent immunological signatures tailored to different pathogens","volume":"6","author":"Knudsen","year":"2016","journal-title":"Sci Rep"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20022144","article-title":"B cell receptor-independent stimuli trigger immunoglobulin (Ig) class switch recombination and production of IgG autoantibodies by anergic self-reactive b cells","volume":"197","author":"Phan","year":"2003","journal-title":"J Exp Med"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007","article-title":"Limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1064","article-title":"WikiPathways: a multifaceted pathway database bridging metabolomics to other omics research","volume":"46","author":"Slenter","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"B28","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/ng1180","article-title":"PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes","volume":"34","author":"Mootha","year":"2003","journal-title":"Nat Genet"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B31","doi-asserted-by":"crossref","first-page":"RESEARCH0034","DOI":"10.1186\/gb-2002-3-7-research0034","article-title":"Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes","volume":"3","author":"Vandesompele","year":"2002","journal-title":"Genome Biol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/nature07345","article-title":"SAP-controlled T-b cell interactions underlie germinal centre formation","volume":"455","author":"Qi","year":"2008","journal-title":"Nature"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1021\/bc9002794","article-title":"Single-step conjugation of bioactive peptides to proteins via a self-contained succinimidyl bis-arylhydrazone","volume":"20","author":"Phillips","year":"2009","journal-title":"Bioconjug Chem"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0099127","article-title":"PPARgamma negatively regulates T cell activation to prevent follicular helper T cells and germinal center formation","volume":"9","author":"Park","year":"2014","journal-title":"PloS One"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-04-154682","article-title":"Interleukin-6\/STAT3 signaling regulates the ability of naive T cells to acquire b-cell help capacities","volume":"113","author":"Eddahri","year":"2009","journal-title":"Blood"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxp041","article-title":"IL-6 produced by immune complex-activated follicular dendritic cells promotes germinal center reactions, IgG responses and somatic hypermutation","volume":"21","author":"Wu","year":"2009","journal-title":"Int Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.171.4.1684","article-title":"Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals","volume":"171","author":"Cassese","year":"2003","journal-title":"J Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20072057","article-title":"Development and characterization of IL-21-producing CD4+ T cells","volume":"205","author":"Suto","year":"2008","journal-title":"J Exp Med"},{"key":"B39","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1084\/jem.20081571","article-title":"The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells","volume":"206","author":"Dienz","year":"2009","journal-title":"J Exp Med"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2008.06.001","article-title":"A fundamental role for interleukin-21 in the generation of T follicular helper cells","volume":"29","author":"Vogelzang","year":"2008","journal-title":"Immunity"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2008.05.009","article-title":"Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages","volume":"29","author":"Nurieva","year":"2008","journal-title":"Immunity"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20091738","article-title":"IL-21 acts directly on b cells to regulate bcl-6 expression and germinal center responses","volume":"207","author":"Linterman","year":"2010","journal-title":"J Exp Med"},{"key":"B43","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1093\/intimm\/dxp112","article-title":"IL-21 and T follicular helper cells","volume":"22","author":"Spolski","year":"2010","journal-title":"Int Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20201555","article-title":"Enhanced IL-2 in early life limits the development of TFH and protective antiviral immunity","volume":"218","author":"Pyle","year":"2021","journal-title":"J Exp Med"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.04.016","article-title":"Human dendritic cells induce the differentiation of interleukin-21-producing T follicular helper-like cells through interleukin-12","volume":"31","author":"Schmitt","year":"2009","journal-title":"Immunity"},{"key":"B46","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1016\/j.immuni.2009.07.005","article-title":"Type I interferon signaling in dendritic cells stimulates the development of lymph-node-resident T follicular helper cells","volume":"31","author":"Cucak","year":"2009","journal-title":"Immunity"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2012.17","article-title":"IL-6 triggers IL-21 production by human CD4+ T cells to drive STAT3-dependent plasma cell differentiation in b cells","volume":"90","author":"Diehl","year":"2012","journal-title":"Immunol Cell Biol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.03049","article-title":"IL-6 impairs vaccine responses in neonatal mice","volume":"9","author":"Yang","year":"2018","journal-title":"Front Immunol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2425","article-title":"Foxp3+ follicular regulatory T cells control the germinal center response","volume":"17","author":"Linterman","year":"2011","journal-title":"Nat Med"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1705551114","article-title":"A distinct subpopulation of CD25(-) T-follicular regulatory cells localizes in the germinal centers","volume":"114","author":"Wing","year":"2017","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2426","article-title":"Follicular regulatory T cells expressing Foxp3 and bcl-6 suppress germinal center reactions","volume":"17","author":"Chung","year":"2011","journal-title":"Nat Med"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2012.06.005","article-title":"Mincle is not essential for controlling mycobacterium tuberculosis infection","volume":"218","author":"Heitmann","year":"2013","journal-title":"Immunobiology"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.2174\/1874312901812010030","article-title":"High secretion of interleukin-6 and increased MINCLE receptor expression upon exposure to mycobacterial cord factor analog trehalose-6, 6-dibehenate (TDB) in patients with takayasu arteritis","volume":"12","author":"Gupta","year":"2018","journal-title":"Open Rheumatol J"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1084\/jem.188.10.1895","article-title":"Interleukin 6 influences germinal center development and antibody production via a contribution of C3 complement component","volume":"188","author":"Kopf","year":"1998","journal-title":"J Exp Med"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0802771","article-title":"Dendritic cells and monocyte\/macrophages that create the IL-6\/APRIL-rich lymph node microenvironments where plasmablasts mature","volume":"182","author":"Mohr","year":"2009","journal-title":"J Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1155200\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T08:54:57Z","timestamp":1680252897000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1155200\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,31]]},"references-count":55,"alternative-id":["10.3389\/fimmu.2023.1155200"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1155200","relation":{},"ISSN":["1664-3224"],"issn-type":[{"type":"electronic","value":"1664-3224"}],"subject":[],"published":{"date-parts":[[2023,3,31]]},"article-number":"1155200"}}