{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T23:11:53Z","timestamp":1771629113708,"version":"3.50.1"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,6]],"date-time":"2022-01-06T00:00:00Z","timestamp":1641427200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["KR3615\/1-1, HO2009\/11-1"],"award-info":[{"award-number":["KR3615\/1-1, HO2009\/11-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["01KA1601"],"award-info":[{"award-number":["01KA1601"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009139","name":"Deutsches Zentrum f\u00fcr Infektionsforschung","doi-asserted-by":"publisher","award":["TI03.907_00"],"award-info":[{"award-number":["TI03.907_00"]}],"id":[{"id":"10.13039\/100009139","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Worldwide, more than 200 million people are infected with filariae which can cause severe symptoms leading to reduced quality of life and contribute to disability-adjusted life years (DALYs). In particular, lymphatic filariasis (LF) caused by <jats:italic>Wuchereria bancrofti<\/jats:italic> can lead to lymphedema (LE) and consequently presents a serious health problem. To understand why only a fraction of the infected individuals develop pathology, it is essential to understand how filariae regulate host immunity. The central role of T cells for immunity against filariae has been shown in several studies. However, there is little knowledge about T cell exhaustion, which causes T cell dysfunction and impaired immune responses, in this group of individuals. Recently, we showed that LE patients from Ghana harbor distinct patterns of exhausted effector and memory CD8<jats:sup>+<\/jats:sup> T cell subsets. Based on these findings, we now characterized CD4<jats:sup>+<\/jats:sup> T cell subsets from the same Ghanaian patient cohort by analyzing distinct markers within a 13-colour flow cytometry panel. We revealed that LE patients had increased frequencies of CD4<jats:sup>+<\/jats:sup> T cells expressing exhaustion-associated receptors such as KLRG-1, TIM-3 and PD-1 compared to healthy endemic normal and <jats:italic>W.\u00a0bancrofti<\/jats:italic>-infected individuals. Moreover, CD4<jats:sup>+<\/jats:sup> T cells in LE patients were characterized by distinct co-expression patterns of inhibitory receptors. Collectively with the previous findings on CD8<jats:sup>+<\/jats:sup> T cell exhaustion patterns, the data shown here demonstrates that filarial LE patients harbor distinct subsets of exhausted T cells. Thus, T cell exhaustion patterns in LE patients need attention especially in regards to susceptibility of concomitant infections and should be taken into consideration for LE management measures.<\/jats:p>","DOI":"10.3389\/fcimb.2021.767306","type":"journal-article","created":{"date-parts":[[2022,1,6]],"date-time":"2022-01-06T05:37:54Z","timestamp":1641447474000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Filarial Lymphedema Patients Are Characterized by Exhausted CD4+ T Cells"],"prefix":"10.3389","volume":"11","author":[{"given":"Sacha","family":"Horn","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuel","family":"Ritter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathrin","family":"Arndts","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dennis","family":"Borrero-Wolff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Wiszniewsky","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda Batsa","family":"Debrah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander Y.","family":"Debrah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jubin","family":"Osei-Mensah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mkunde","family":"Chachage","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Achim","family":"Hoerauf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Inge","family":"Kroidl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura E.","family":"Layland","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1179\/136485910X12786389891407","article-title":"Induction of Immunoglobulin G4 in Human Filariasis: An Indicator of Immunoregulation","volume":"104","author":"Adjobimey","year":"2010","journal-title":"Ann. Trop. Med. Parasitol."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201545905","article-title":"Fasciola Hepatica Tegumental Antigens Induce Anergic-Like T Cells via Dendritic Cells in a Mannose Receptor-Dependent Manner","volume":"46","author":"Aldridge","year":"2016","journal-title":"Eur J Immunol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"e1611","DOI":"10.1371\/journal.pntd.0001611","article-title":"Elevated Adaptive Immune Responses are Associated With Latent Infections of Wuchereria Bancrofti","volume":"6","author":"Arndts","year":"2012","journal-title":"PloS Negl. Trop. Dis."},{"key":"B4","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1186\/s13071-015-0786-5","article-title":"Reductions in Microfilaridermia by Repeated Ivermectin Treatment are Associated With Lower Plasmodium-Specific Th17 Immune Responses in Onchocerca Volvulus-Infected Individuals","volume":"8","author":"Arndts","year":"2015","journal-title":"Parasit. Vectors"},{"key":"B5","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1186\/s12889-021-10170-8","article-title":"Financial Burden Impact Quality of Life Among Lymphatic Filariasis Patients","volume":"21","author":"Asiedu","year":"2021","journal-title":"BMC Public Health"},{"key":"B6","doi-asserted-by":"publisher","first-page":"e420","DOI":"10.1371\/journal.pntd.0000420","article-title":"Filarial Lymphedema is Characterized by Antigen-Specific Th1 and Th17 Proinflammatory Responses and a Lack of Regulatory T Cells","volume":"3","author":"Babu","year":"2009","journal-title":"PLoS Negl. Trop. Dis."},{"key":"B7","doi-asserted-by":"publisher","first-page":"3248","DOI":"10.4049\/jimmunol.176.5.3248","article-title":"Regulatory Networks Induced by Live Parasites Impair Both Th1 and Th2 Pathways in Patent Lymphatic Filariasis: Implications for Parasite Persistence","volume":"176","author":"Babu","year":"2006","journal-title":"J. Immunol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1007\/s00281-012-0346-4","article-title":"Immunopathogenesis of Lymphatic Filarial Disease","volume":"34","author":"Babu","year":"2012","journal-title":"Semin. Immunopathol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1111\/pim.12081","article-title":"Immunology of Lymphatic Filariasis","volume":"36","author":"Babu","year":"2014","journal-title":"Parasite Immunol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"884","DOI":"10.4269\/ajtmh.2010.10-0039","article-title":"Elevated Levels of Plasma Angiogenic Factors are Associated With Human Lymphatic Filarial Infections","volume":"83","author":"Bennuru","year":"2010","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"B11","doi-asserted-by":"publisher","first-page":"e1000688","DOI":"10.1371\/journal.ppat.1000688","article-title":"Lymphangiogenesis and Lymphatic Remodeling Induced by Filarial Parasites: Implications for Pathogenesis","volume":"5","author":"Bennuru","year":"2009","journal-title":"PLoS Pathog."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1172\/JCI10182","article-title":"Chronic Immune Activation Associated With Intestinal Helminth Infections Results in Impaired Signal Transduction and Anergy","volume":"106","author":"Borkow","year":"2000","journal-title":"J. Clin. Invest."},{"key":"B13","doi-asserted-by":"publisher","first-page":"e30947","DOI":"10.7554\/eLife.30947","article-title":"Myeloid Cell Recruitment Versus Local Proliferation Differentiates Susceptibility From Resistance to Filarial Infection","volume":"7","author":"Campbell","year":"2018","journal-title":"Elife"},{"key":"B14","doi-asserted-by":"publisher","first-page":"e94603","DOI":"10.1371\/journal.pone.0094603","article-title":"Incidence of Active Pulmonary Tuberculosis in Patients With Coincident Filarial and\/or Intestinal Helminth Infections Followed Longitudinally in South India","volume":"9","author":"Chatterjee","year":"2014","journal-title":"PLoS One"},{"key":"B15","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1016\/j.jvsv.2019.11.014","article-title":"The Clinical Characteristics of Lower Extremity Lymphedema in 440 Patients","volume":"8","author":"Dean","year":"2020","journal-title":"J. Vasc. Surg. Venous Lymphat. Disord."},{"key":"B16","doi-asserted-by":"publisher","first-page":"e92","DOI":"10.1371\/journal.ppat.0020092","article-title":"Doxycycline Reduces Plasma VEGF-C\/sVEGFR-3 and Improves Pathology in Lymphatic Filariasis","volume":"2","author":"Debrah","year":"2006","journal-title":"PLoS Pathog."},{"key":"B17","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1186\/s12865-019-0309-9","article-title":"CD4(+) T Cell Exhaustion Revealed by High PD-1 and LAG-3 Expression and the Loss of Helper T Cell Function in Chronic Hepatitis B","volume":"20","author":"Dong","year":"2019","journal-title":"BMC Immunol."},{"key":"B18","first-page":"13","article-title":"Assessment of Chronic Lymphoedema","volume-title":"Basic Lymphoedema Management: Treatment and Prevention of Problems Associated With Lymphatic Filariasis","author":"Dreyer","year":"2002"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1591","DOI":"10.1136\/bmj.318.7198.1591","article-title":"Risk Factors for Erysipelas of the Leg (Cellulitis): Case-Control Study","volume":"318","author":"Dupuy","year":"1999","journal-title":"BMJ"},{"key":"B20","doi-asserted-by":"publisher","first-page":"e1004375","DOI":"10.1371\/journal.ppat.1004375","article-title":"Helminth Infections Coincident With Active Pulmonary Tuberculosis Inhibit Mono- and Multifunctional CD4+ and CD8+ T Cell Responses in a Process Dependent on IL-10","volume":"10","author":"George","year":"2014","journal-title":"PLoS Pathog."},{"key":"B21","doi-asserted-by":"publisher","first-page":"e1005177","DOI":"10.1371\/journal.ppat.1005177","article-title":"CD39 Expression Identifies Terminally Exhausted CD8+ T Cells","volume":"11","author":"Gupta","year":"2015","journal-title":"PLoS Pathog."},{"key":"B22","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1080\/00034983.1996.11813024","article-title":"The Economic Burden of Lymphatic Filariasis in Northern Ghana","volume":"90","author":"Gyapong","year":"1996","journal-title":"Ann. Trop. Med. Parasitol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1111\/j.1365-3024.2005.00792.x","article-title":"Immunomodulation by Filarial Nematodes","volume":"27","author":"Hoerauf","year":"2005","journal-title":"Parasite Immunol."},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.680832","article-title":"Distinct Immune Profiles of Exhausted Effector and Memory CD8+ T Cells in Individuals With Filarial Lymphedema","volume":"11","author":"Horn","year":"2021","journal-title":"Front. Cell Infect. Microbiol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"e0007908","DOI":"10.1371\/journal.pntd.0007908","article-title":"Helminth-Induced Th2 Cell Dysfunction is Distinct From Exhaustion and is Maintained in the Absence of Antigen","volume":"13","author":"Knipper","year":"2019","journal-title":"PLoS Negl. Trop. Dis."},{"key":"B26","doi-asserted-by":"publisher","first-page":"e0007623","DOI":"10.1371\/journal.pntd.0007623","article-title":"Wuchereria Bancrofti Infection is Linked to Systemic Activation of CD4 and CD8 T Cells","volume":"13","author":"Kroidl","year":"2019","journal-title":"PLoS Negl. Trop. Dis."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1912","DOI":"10.1016\/S0140-6736(16)31252-1","article-title":"Effect of Wuchereria Bancrofti Infection on HIV Incidence in Southwest Tanzania: A Prospective Cohort Study","volume":"388","author":"Kroidl","year":"2016","journal-title":"Lancet"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e0006345","DOI":"10.1371\/journal.pntd.0006345","article-title":"Seroepidemiology of Helminths and the Association With Severe Malaria Among Infants and Young Children in Tanzania","volume":"12","author":"Kwan","year":"2018","journal-title":"PLoS Negl. Trop. Dis."},{"key":"B29","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1093\/intimm\/dxh375","article-title":"Increased TGF-Beta, Cbl-B and CTLA-4 Levels and Immunosuppression in Association With Chronic Immune Activation","volume":"18","author":"Leng","year":"2006","journal-title":"Int. Immunol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"5375","DOI":"10.4049\/jimmunol.0904067","article-title":"At Homeostasis Filarial Infections Have Expanded Adaptive T Regulatory But Not Classical Th2 Cells","volume":"184","author":"Metenou","year":"2010","journal-title":"J. Immunol."},{"key":"B31","first-page":"40","article-title":"Skin Changes in Filarial and non-Filarial Lymphoedema of the Lower Extremities","volume":"44","author":"Olszewski","year":"1993","journal-title":"Trop. Med. Parasitol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"7","DOI":"10.4269\/ajtmh.1997.57.7","article-title":"Bacteriologic Studies of Skin, Tissue Fluid, Lymph, and Lymph Nodes in Patients With Filarial Lymphedema","volume":"57","author":"Olszewski","year":"1997","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"B33","first-page":"12","article-title":"Immunomodulation by Filarial Parasites","volume":"1","author":"Rajamanickam","year":"2013","journal-title":"Int. Trends Immun."},{"key":"B34","doi-asserted-by":"publisher","first-page":"e3319","DOI":"10.1371\/journal.pntd.0003319","article-title":"Progress and Impact of 13 Years of the Global Programme to Eliminate Lymphatic Filariasis on Reducing the Burden of Filarial Disease","volume":"8","author":"Ramaiah","year":"2014","journal-title":"PLoS Negl. Trop. Dis."},{"key":"B35","doi-asserted-by":"publisher","first-page":"e0007436","DOI":"10.1371\/journal.pntd.0007436","article-title":"Wuchereria Bancrofti-Infected Individuals Harbor Distinct IL-10-Producing Regulatory B and T Cell Subsets Which are Affected by Anti-Filarial Treatment","volume":"13","author":"Ritter","year":"2019","journal-title":"PLoS Negl. Trop. Dis."},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01002","article-title":"The Chronic Stages of Bovine Fasciola Hepatica are Dominated by CD4 T-Cell Exhaustion","volume":"8","author":"Sachdev","year":"2017","journal-title":"Front. Immunol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"2414","DOI":"10.1016\/j.micinf.2006.05.003","article-title":"Human Bancroftian Filariasis: Immunological Markers of Morbidity and Infection","volume":"8","author":"Satapathy","year":"2006","journal-title":"Microbes Infect."},{"key":"B38","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1016\/0035-9203(67)90162-9","article-title":"A Chronological Study of the Histopathology of Filarial Disease in Cats and Dogs Caused by Brugia Pahangi (Buckley and Edeson 1956))","volume":"61","author":"Schacher","year":"1967","journal-title":"Trans. R. Soc Trop. Med. Hyg."},{"key":"B39","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1146\/annurev.immunol.21.120601.141110","article-title":"T Cell Anergy","volume":"21","author":"Schwartz","year":"2003","journal-title":"Ann. Rev. Immunol."},{"key":"B40","first-page":"301","article-title":"A Preliminary Study of Filariasis Related Acute Adenolymphangitis With Special Reference to Precipitating Factors and Treatment Modalities","volume":"26","author":"Shenoy","year":"1995","journal-title":"Southeast Asian J. Trop. Med. Public Health"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1172\/JCI36534","article-title":"Th2 Cell Hyporesponsiveness During Chronic Murine Schistosomiasis is Cell Intrinsic and Linked to GRAIL Expression","volume":"119","author":"Taylor","year":"2009","journal-title":"J. Clin. Invest."},{"key":"B42","doi-asserted-by":"publisher","first-page":"4924","DOI":"10.4049\/jimmunol.174.8.4924","article-title":"Removal of Regulatory T Cell Activity Reverses Hyporesponsiveness and Leads to Filarial Parasite Clearance In Vivo","volume":"174","author":"Taylor","year":"2005","journal-title":"J. Immunol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"e0008173","DOI":"10.1371\/journal.pntd.0008173","article-title":"The Impact of Leprosy, Podoconiosis and Lymphatic Filariasis on Family Quality of Life: A Qualitative Study in Northwest Ethiopia","volume":"14","author":"van 't Noordende","year":"2020","journal-title":"PloS Negl. Trop. Dis."},{"key":"B44","doi-asserted-by":"publisher","first-page":"e1003215","DOI":"10.1371\/journal.ppat.1003215","article-title":"Th2 Cell-Intrinsic Hypo-Responsiveness Determines Susceptibility to Helminth Infection","volume":"9","author":"van der Werf","year":"2013","journal-title":"PloS Pathog."},{"key":"B45","doi-asserted-by":"publisher","first-page":"e1655","DOI":"10.1371\/journal.pntd.0001655","article-title":"Regulatory T Cells in Human Lymphatic Filariasis: Stronger Functional Activity in Microfilaremics","volume":"6","author":"Wammes","year":"2012","journal-title":"PLoS Negl. Trop. Dis."},{"key":"B46","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1002\/iid3.181","article-title":"Depletion of FoxP3(+) Tregs Improves Control of Larval Echinococcus Multilocularis Infection by Promoting Co-Stimulation and Th1\/17 Immunity","volume":"5","author":"Wang","year":"2017","journal-title":"Immun. Inflamm. Dis."},{"key":"B47","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1038\/ni.2035","article-title":"T Cell Exhaustion","volume":"12","author":"Wherry","year":"2011","journal-title":"Nat. Immunol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1038\/nri3862","article-title":"Molecular and Cellular Insights Into T Cell Exhaustion","volume":"15","author":"Wherry","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"B49","first-page":"55","article-title":"Ending the Neglect to Attain the Sustainable Development Goals\u2013A Road Map for Neglected Tropical Diseases 2021\u20132030","year":"2020","journal-title":"World Health Organ. Geneva"},{"key":"B50","first-page":"497","article-title":"Global Programme to Eliminate Lymphatic Filariasis: Progress Report 2019","volume":"96","year":"2021","journal-title":"Wkly. Epidemiol. Rec."},{"key":"B51","doi-asserted-by":"publisher","first-page":"11153","DOI":"10.1038\/s41598-017-11703-1","article-title":"T-Cell Tolerance and Exhaustion in the Clearance of Echinococcus Multilocularis: Role of Inoculum Size in a Quantitative Hepatic Experimental Model","volume":"7","author":"Zhang","year":"2017","journal-title":"Sci. Rep."}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2021.767306\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,6]],"date-time":"2022-01-06T05:38:05Z","timestamp":1641447485000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2021.767306\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,6]]},"references-count":51,"alternative-id":["10.3389\/fcimb.2021.767306"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2021.767306","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,6]]},"article-number":"767306"}}