{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T21:30:58Z","timestamp":1793741458163,"version":"4.6.1"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,16]],"date-time":"2022-05-16T00:00:00Z","timestamp":1652659200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI116432"],"award-info":[{"award-number":["R01AI116432"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003074","name":"Agencia Nacional de Promoci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","doi-asserted-by":"publisher","award":["PICT 2015-0645"],"award-info":[{"award-number":["PICT 2015-0645"]}],"id":[{"id":"10.13039\/501100003074","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002923","name":"Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002923","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    During infections with protozoan parasites or some viruses, T cell immunosuppression is generated simultaneously with a high B cell activation. It has been described that, as well as producing antibodies, plasmablasts, the differentiation product of activated B cells, can condition the development of protective immunity in infections. Here, we show that, in\n                    <jats:italic>T. cruzi<\/jats:italic>\n                    infection, all the plasmablasts detected during the acute phase of the infection had higher surface expression of PD-L1 than other mononuclear cells. PD-L1\n                    <jats:sup>hi<\/jats:sup>\n                    plasmablasts were induced\n                    <jats:italic>in vivo<\/jats:italic>\n                    in a BCR-specific manner and required help from Bcl-6\n                    <jats:sup>+<\/jats:sup>\n                    CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells. PD-L1\n                    <jats:sup>hi<\/jats:sup>\n                    expression was not a characteristic of all antibody-secreting cells since plasma cells found during the chronic phase of infection expressed PD-L1 but at lower levels. PD-L1\n                    <jats:sup>hi<\/jats:sup>\n                    plasmablasts were also present in mice infected with\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    or with lymphocytic choriomeningitis virus, but not in mice with autoimmune disorders or immunized with T cell-dependent antigens.\n                    <jats:italic>In vitro<\/jats:italic>\n                    experiments showed that PD-L1\n                    <jats:sup>hi<\/jats:sup>\n                    plasmablasts suppressed the T cell response, partially\n                    <jats:italic>via<\/jats:italic>\n                    PD-L1. Thus, this study reveals that extrafollicular PD-L1\n                    <jats:sup>hi<\/jats:sup>\n                    plasmablasts, whose peaks of response precede the peak of germinal center response, may have a modulatory function in infections, thus influencing T cell response.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2022.828734","type":"journal-article","created":{"date-parts":[[2022,5,16]],"date-time":"2022-05-16T04:27:27Z","timestamp":1652675247000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Extrafollicular Plasmablasts Present in the Acute Phase of Infections Express High Levels of PD-L1 and Are Able to Limit T Cell Response"],"prefix":"10.3389","volume":"13","author":[{"given":"Melisa Gorosito","family":"Serr\u00e1n","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Facundo Fiocca","family":"Vernengo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Almada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristian G.","family":"Beccaria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamila","family":"Gazzoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo F.","family":"Canete","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan A.","family":"Roco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimena Tosello","family":"Boari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Cecilia","family":"Ramello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Wehrens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeping","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elina I.","family":"Zuniga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina L.","family":"Montes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian A.","family":"Cockburn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva V. Acosta","family":"Rodriguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carola G.","family":"Vinuesa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Gruppi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00212\/abstract","article-title":"Escaping Deleterious Immune Response in Their Hosts: Lessons From Trypanosomatids","volume":"7","author":"Geiger","year":"2016","journal-title":"Front Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-virology-100114-055226","article-title":"Innate and Adaptive Immune Regulation During Chronic Viral Infections","volume":"2","author":"Zuniga","year":"2015","journal-title":"Annu Rev Virol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201343606","article-title":"Myeloid-Derived Suppressor Cells are Key Players in the Resolution of Inflammation During a Model of Acute Infection","volume":"44","author":"Arocena","year":"2014","journal-title":"Eur J Immunol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2012\/829139","article-title":"Trypanosoma Cruzi SSP4 Amastigote Protein Induces Expression of Immunoregulatory and Immunosuppressive Molecules in Peripheral Blood Mononuclear Cells","volume":"2012","author":"Mor\u00e1n-Utrera","year":"2012","journal-title":"J Trop Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2010.04.016","article-title":"Central Role of Extracellular Signal-Regulated Kinase and Toll-Like Receptor 4 in IL-10 Production in Regulatory Dendritic Cells Induced by Trypanosoma Cruzi","volume":"47","author":"Poncini","year":"2010","journal-title":"Mol Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01931-06","article-title":"Trypanosoma Cruzi Infection Induces Differential Modulation of Costimulatory Molecules and Cytokines by Monocytes and T Cells From Patients With Indeterminate and Cardiac Chagas\u2019 Disease","volume":"75","author":"Souza","year":"2007","journal-title":"Infect Immun"},{"key":"B7","doi-asserted-by":"crossref","DOI":"10.1128\/IAI.01047-10","article-title":"Regulation of Trypanosoma Cruzi-Induced Myocarditis by Programmed Death Cell Receptor 1","volume-title":"Infect Immun","author":"Gutierrez","year":"2011"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/70932","article-title":"B7-H1, A Third Member of the B7 Family, Co-Stimulates T-Cell Proliferation and Interleukin-10 Secretion","volume":"5","author":"Dong","year":"1999","journal-title":"Nat Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/85330","article-title":"PD-L2 is a Second Ligand for PD-1 and Inhibits T Cell Activation","volume":"2","author":"Latchman","year":"2001","journal-title":"Nat Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2180","article-title":"Therapeutic Blockade of PD-L1 and LAG-3 Rapidly Clears Established Blood-Stage Plasmodium Infection","volume":"13","author":"Butler","year":"2012","journal-title":"Nat Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/nature05115","article-title":"PD-1 Expression on HIV-Specific T Cells is Associated With T-Cell Exhaustion and Disease Progression","volume":"443","author":"Day","year":"2006","journal-title":"Nature"},{"key":"B12","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1002\/JLB.5HI0917-360R","article-title":"Frontline Science: Anti-PD-L1 Protects Against Infection With Common Bacterial Pathogens After Burn Injury","volume":"103","author":"Patil","year":"2018","journal-title":"J Leukoc Biol"},{"key":"B13","first-page":"e1005224","article-title":"PD-L1 Expression on Retrovirus-Infected Cells Mediates Immune Escape From CD8+ T Cell Killing","volume-title":"PLoS Pathog","author":"Akhmetzyanova","year":"2015"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201646875","article-title":"Immune Checkpoints and Their Inhibition in Cancer and Infectious Diseases","volume":"47","author":"Dyck","year":"2017","journal-title":"Eur J Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2015.07.005","article-title":"Salmonella Impairs CD8 T Cell Response Through PD-1: PD-L Axis","volume":"220","author":"L\u00f3pez-Medina","year":"2015","journal-title":"Immunobiology"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20071949","article-title":"Enhancing Therapeutic Vaccination by Blocking PD-1\u2013Mediated Inhibitory Signals During Chronic Infection","volume":"205","author":"Ha","year":"2008","journal-title":"J Exp Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1172\/JCI67008","article-title":"PD-L1 Blockade Synergizes With IL-2 Therapy in Reinvigorating Exhausted T Cells","volume":"123","author":"West","year":"2013","journal-title":"J Clin Invest"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/nature14395","article-title":"Immunosuppressive Plasma Cells Impede T-Cell-Dependent Immunogenic Chemotherapy","volume":"521","author":"Shalapour","year":"2015","journal-title":"Nature"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01548","article-title":"Unconventional Pro-Inflammatory CD4+ T Cell Response in B Cell-Deficient Mice Infected With Trypanosoma Cruzi","volume":"8","author":"Gorosito Serr\u00e1n","year":"2017","journal-title":"Front Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2010.03347.x","article-title":"Trypanosoma Cruzi Infection Induces a Massive Extrafollicular and Follicular Splenic B-Cell Response Which is a High Source of non-Parasite-Specific Antibodies: B-Cell Response to T","volume":"132","author":"Bermejo","year":"2011","journal-title":"Cruzi Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20102065","article-title":"B Cell Priming for Extrafollicular Antibody Responses Requires Bcl-6 Expression by T Cells","volume":"208","author":"Lee","year":"2011","journal-title":"J Exp Med"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1300378","article-title":"Insights Into the Role of Bcl6 in Follicular Th Cells Using a New Conditional Mutant Mouse Model","volume":"191","author":"Hollister","year":"2013","journal-title":"JI"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2569","article-title":"Trypanosoma Cruzi Trans-Sialidase Initiates a Program Independent of the Transcription Factors Ror\u03b3t and Ahr That Leads to IL-17 Production by Activated B Cells","volume":"14","author":"Bermejo","year":"2013","journal-title":"Nat Immunol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1146\/annurev.immunol.26.021607.090331","article-title":"PD-1 and Its Ligands in Tolerance and Immunity","volume":"26","author":"Keir","year":"2008","journal-title":"Annu Rev Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.8.4911-4927.2003","article-title":"Viral Persistence Alters CD8 T-Cell Immunodominance and Tissue Distribution and Results in Distinct Stages of Functional Impairment","volume":"77","author":"Wherry","year":"2003","journal-title":"J Virol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20060087","article-title":"Antigen Recognition Strength Regulates the Choice Between Extrafollicular Plasma Cell and Germinal Center B Cell Differentiation","volume":"203","author":"Paus","year":"2006","journal-title":"J Exp Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2014.02.027","article-title":"Dendritic Cells With an Increased PD-L1 by TGF-\u03b2 Induce T Cell Anergy for the Cytotoxicity of Hepatocellular Carcinoma Cells","volume":"20","author":"Song","year":"2014","journal-title":"Int Immunopharmacol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3892\/or.2017.5894","article-title":"Chemotherapy Enhances Programmed Cell Death 1\/Ligand 1 Expression via TGF-\u03b2 Induced Epithelial Mesenchymal Transition in non-Small Cell Lung Cancer","volume":"38","author":"Funaki","year":"2017","journal-title":"Oncol Rep"},{"key":"B29","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.imlet.2017.02.006","article-title":"Inflammatory Cytokines IL-17 and TNF-\u03b1 Up-Regulate PD-L1 Expression in Human Prostate and Colon Cancer Cells","volume":"184","author":"Wang","year":"2017","journal-title":"Immunol Lett"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00580-09","article-title":"Pharmacological Inhibition of Transforming Growth Factor \u03b2 Signaling Decreases Infection and Prevents Heart Damage in Acute Chagas\u2019 Disease","volume":"53","author":"Waghabi","year":"2009","journal-title":"Antimicrob Agents Chemother"},{"key":"B31","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1016\/j.cell.2017.11.036","article-title":"Initiation of Antiviral B Cell Immunity Relies on Innate Signals From Spatially Positioned NKT Cells","volume":"172","author":"Gaya","year":"2018","journal-title":"Cell"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-10-250126","article-title":"Mast Cells Enhance Proliferation of B Lymphocytes and Drive Their Differentiation Toward IgA-Secreting Plasma Cells","volume":"115","author":"Merluzzi","year":"2010","journal-title":"Blood"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1088","DOI":"10.1016\/j.immuni.2019.10.004","article-title":"Liver Is a Generative Site for the B Cell Response to Ehrlichia Muris","volume":"51","author":"Trivedi","year":"2019","journal-title":"Immunity"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/nature12979","article-title":"IL-35-Producing B Cells are Critical Regulators of Immunity During Autoimmune and Infectious Diseases","volume":"507","author":"Shen","year":"2014","journal-title":"Nature"},{"key":"B35","doi-asserted-by":"publisher","first-page":"ftv082","DOI":"10.1093\/femspd\/ftv082","article-title":"Immunity and Immune Modulation in Trypanosoma Cruzi Infection","volume":"73","author":"Cardillo","year":"2015","journal-title":"Pathog Dis"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3083.1988.tb01487.x","article-title":"Most B Cells in Acute Trypanosoma Cruzi Infection Lack Parasite Specificity","volume":"28","author":"Minoprio","year":"1988","journal-title":"Scand J Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2012.08.010","article-title":"IgA Plasma Cells Express the Negative Regulatory Co-Stimulatory Molecule Programmed Cell Death 1 Ligand and Have a Potential Tolerogenic Role in the Intestine","volume":"425","author":"Doi","year":"2012","journal-title":"Biochem Biophys Res Commun"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-020711-074934","article-title":"Immune Regulatory Function of B Cells","volume":"30","author":"Mauri","year":"2012","journal-title":"Annu Rev Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.10.016","article-title":"Interleukin-10-Producing Plasmablasts Exert Regulatory Function in Autoimmune Inflammation","volume":"41","author":"Matsumoto","year":"2014","journal-title":"Immunity"},{"key":"B40","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1038\/s41590-020-0678-5","article-title":"Infection-Induced Plasmablasts Are a Nutrient Sink That Impairs Humoral Immunity to Malaria","volume":"21","author":"Vijay","year":"2020","journal-title":"Nat Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02241","article-title":"PD-L1+ Regulatory B Cells Are Significantly Decreased in Rheumatoid Arthritis Patients and Increase After Successful Treatment","volume":"9","author":"Zacca","year":"2018","journal-title":"Front Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-19-0240","article-title":"Myeloid-Derived Suppressive Cells Promote B Cell\u2013Mediated Immunosuppression via Transfer of PD-L1 in Glioblastoma","volume":"7","author":"Lee-Chang","year":"2019","journal-title":"Cancer Immunol Res"},{"key":"B43","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1590\/S0100-879X2011007500005","article-title":"Evasion of Immune Responses by Trypanosoma Cruzi, the Etiological Agent of Chagas Disease","volume":"44","author":"DosReis","year":"2011","journal-title":"Braz J Med Biol Res"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1301450","article-title":"Acute Plasmodium Chabaudi Infection Dampens Humoral Responses to a Secondary T-Dependent Antigen But Enhances Responses to a Secondary T-Independent Antigen","volume":"191","author":"Wilmore","year":"2013","journal-title":"JI"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/nature04444","article-title":"Restoring Function in Exhausted CD8 T Cells During Chronic Viral Infection","volume":"439","author":"Barber","year":"2006","journal-title":"Nature"},{"key":"B46","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1002\/eji.201948286","article-title":"LCMV-Specific CD4 T Cell Dependent Polyclonal B-Cell Activation Upon Persistent Viral Infection is Short Lived and Extrafollicular","volume":"50","author":"Greczmiel","year":"2020","journal-title":"Eur J Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200636516","article-title":"Dynamics and Magnitude of Virus-Induced Polyclonal B Cell Activation Mediated by BCR-Independent Presentation of Viral Antigen","volume":"37","author":"Jellison","year":"2007","journal-title":"Eur J Immunol"},{"key":"B48","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.00447-20","article-title":"CD8 + T Cell Immunity Is Compromised by Anti-CD20 Treatment and Rescued by Interleukin-17a","volume-title":"Mbio","author":"Fiocca Vernengo","year":"2020"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1128\/iai.65.2.349-357.1997","article-title":"Identification of the Gene Family Encoding the 160-Kilodalton Trypanosoma Cruzi Complement Regulatory Protein","volume":"65","author":"Norris","year":"1997","journal-title":"Infect Immun"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1084\/jem.160.2.521","article-title":"Selection of Genetic Variants of Lymphocytic Choriomeningitis Virus in Spleens of Persistently Infected Mice. Role in Suppression of Cytotoxic T Lymphocyte Response and Viral Persistence","volume":"160","author":"Ahmed","year":"1984","journal-title":"J Exp Med"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.828734\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,16]],"date-time":"2022-05-16T04:27:34Z","timestamp":1652675254000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.828734\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,16]]},"references-count":50,"alternative-id":["10.3389\/fimmu.2022.828734"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.828734","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,16]]},"article-number":"828734"}}