{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T02:46:35Z","timestamp":1772246795431,"version":"3.50.1"},"reference-count":120,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T00:00:00Z","timestamp":1666742400000},"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":["NHLBI R00HL116234, NHGRI R01HG010318, NHGRI R21HG010108"],"award-info":[{"award-number":["NHLBI R00HL116234, NHGRI R01HG010318, NHGRI R21HG010108"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001422","name":"American Society of Hematology","doi-asserted-by":"publisher","award":["C. Glenn Barber fund"],"award-info":[{"award-number":["C. Glenn Barber fund"]}],"id":[{"id":"10.13039\/100001422","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    CD3-epsilon(CD3e) immunotoxins (IT), a promising precision reagent for various clinical conditions requiring effective depletion of T cells, often shows limited treatment efficacy for largely unknown reasons. Tissue-resident T cells that persist in peripheral tissues have been shown to play pivotal roles in local and systemic immunity, as well as transplant rejection, autoimmunity and cancers. The impact of\u00a0CD3e-IT\u00a0treatment on these local cells, however, remains poorly understood. Here, using a new murine\u00a0testing model, we demonstrate a substantial enrichment of tissue-resident Foxp3+ Tregs following CD3e-IT treatment. Differential surface expression of CD3e among T-cell subsets appears to be a main driver of Treg enrichment in\u00a0CD3e-IT treatment. The surviving Tregs in\u00a0CD3e-IT-treated mice\u00a0were mostly the CD3e\n                    <jats:sup>dim<\/jats:sup>\n                    CD62L\n                    <jats:sup>lo<\/jats:sup>\n                    \u00a0effector phenotype, but the levels of this phenotype markedly varied among different lymphoid and nonlymphoid organs. We also found notable variations in surface\u00a0CD3e levels among tissue-resident T cells of different organs, and these variations\u00a0drive CD3e-IT to uniquely reshape T-cell compositions in local organs. The functions of organs and anatomic locations (lymph nodes)\u00a0also affected the efficacy of CD3e-IT. The multi-organ pharmacodynamics of CD3e-IT and potential treatment resistance mechanisms identified in this study may generate new opportunities to further improve this promising treatment.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2022.1011190","type":"journal-article","created":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T05:07:41Z","timestamp":1666760861000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["CD3e-immunotoxin spares CD62Llo Tregs and reshapes organ-specific T-cell composition by preferentially depleting CD3ehi T cells"],"prefix":"10.3389","volume":"13","author":[{"given":"Shihyoung","family":"Kim","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rajni Kant","family":"Shukla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alice","family":"Baek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophie G.","family":"Cressman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Golconda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ga-Eun","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyewon","family":"Choi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John C.","family":"Reneau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhirui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christene A.","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Namal P. M.","family":"Liyanage","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanggu","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"794","DOI":"10.3324\/haematol.2015.123711","article-title":"Resimmune, an anti-CD3\u03f5 recombinant immunotoxin, induces durable remissions in patients with cutaneous T-cell lymphoma","volume":"100","author":"Frankel","year":"2015","journal-title":"Haematologica"},{"key":"B2","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1006\/cimm.1997.1096","article-title":"Depletion of T lymphocytes with immunotoxin retards the progress of experimental allergic encephalomyelitis in rhesus monkeys","volume":"177","author":"Hu","year":"1997","journal-title":"Cell Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1097\/00007890-200203270-00008","article-title":"Long-term kidney graft survival by delayed T cell ablative treatment in rhesus monkeys1,2","volume":"73","author":"Jonker","year":"2002","journal-title":"Transplantation"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.12560","article-title":"Vascularized composite allograft tolerance across MHC barriers in a Large animal model","volume":"14","author":"Leonard","year":"2014","journal-title":"Am J Transplant"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1172\/JCI7913","article-title":"Stable mixed chimerism and tolerance using a nonmyeloablative preparative regimen in a large-animal model","volume":"105","author":"Huang","year":"2000","journal-title":"J Clin Invest"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1021\/bc200230h","article-title":"Development of a diphtheria toxin based antiporcine CD3 recombinant immunotoxin","volume":"22","author":"Wang","year":"2011","journal-title":"Bioconjugate Chem"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/S0003-4975(00)01564-2","article-title":"Mixed hematopoietic chimerism induces long-term tolerance to cardiac allografts in miniature swine","volume":"70","author":"Schwarze","year":"2000","journal-title":"Ann Thorac Surg"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/14.12.1035","article-title":"Improved binding of a bivalent single-chain immunotoxin results in increased efficacy for in vivo T-cell depletion","volume":"14","author":"Thompson","year":"2001","journal-title":"Protein Eng Des Sel"},{"key":"B9","doi-asserted-by":"publisher","first-page":"794","DOI":"10.3324\/haematol.2015.123711","article-title":"Resimmune, an anti-CD3 recombinant immunotoxin, induces durable remissions in patients with cutaneous T-cell lymphoma","volume":"100","author":"Frankel","year":"2015","journal-title":"Haematologica"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.47.28037","article-title":"An anti-CD3 single-chain immunotoxin with a truncated diphtheria toxin avoids inhibition by pre-existing antibodies in human blood","volume":"270","author":"Thompson","year":"1995","journal-title":"J Biol Chem"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1111\/jdv.12299","article-title":"Genetic markers associated with progression in early mycosis fungoides","volume":"28","author":"Johnson","year":"2014","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-05-504308","article-title":"PLCG1 mutations in cutaneous T-cell lymphomas","volume":"123","author":"Vaqu\u00e9","year":"2014","journal-title":"Blood"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2019.10.037","article-title":"Critical issues in the development of immunotoxins for anticancer therapy","volume":"109","author":"Kim","year":"2020","journal-title":"J Pharm Sci"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-008-0457-x","article-title":"Preclinical studies in rats and squirrel monkeys for safety evaluation of the bivalent anti-human T cell immunotoxin, A-dmDT390\u2013bisFv(UCHT1)","volume":"57","author":"Woo","year":"2008","journal-title":"Cancer Immunol Immunother"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1097\/00007890-199909150-00016","article-title":"Activation of T lymphocytes for adhesion and cytokine expression by toxin-conjugated anti-CD3 monoclonal antibodies","volume":"68","author":"Hamawy","year":"1999","journal-title":"Transplantation"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.trim.2012.05.003","article-title":"Effect of pre-existing anti-diphtheria toxin antibodies on T cell depletion levels following diphtheria toxin-based recombinant anti-monkey CD3 immunotoxin treatment","volume":"27","author":"Matar","year":"2012","journal-title":"Transpl Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00242","article-title":"Differential sensitivity of regulatory and effector T cells to cell death: A prerequisite for transplant tolerance","volume":"6","author":"You","year":"2015","journal-title":"Front Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1401551","article-title":"Heterogeneous CD3 expression levels in differing T cell subsets correlate with the In vivo Anti-CD3\u2013mediated T cell modulation","volume":"194","author":"Valle","year":"2015","journal-title":"JI"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1521-4141(200005)30:5<1469::AID-IMMU1469>3.0.CO;2-V","article-title":"Variability of invariant mouse CD3\u03f5 chains detected by anti-CD3 antibodies","volume":"30","author":"Criado","year":"2000","journal-title":"Eur J Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.1112584","article-title":"Characteristics of TCR\/CD3 complex CD3\u03b5 chains of regulatory CD4+ T (Treg) lymphocytes: Role in treg differentiation in vitro and impact on treg in vivo","volume":"95","author":"Rojo","year":"2014","journal-title":"J Leukocyte Biol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/sj.icb.7100042","article-title":"Polymorphisms of CD3\u03f5 in cynomolgus and rhesus monkeys and their relevance to anti-CD3 antibodies and immunotoxins","volume":"85","author":"Liu","year":"2007","journal-title":"Immunol Cell Biol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3390\/biom10070979","article-title":"Mechanisms of resistance to immunotoxins containing pseudomonas exotoxin a in cancer therapy","volume":"10","author":"Dieffenbach","year":"2020","journal-title":"Biomolecules"},{"key":"B23","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1097\/00002371-199603000-00001","article-title":"A new reagent for the induction of T-cell depletion, anti-CD3-CRM9","volume":"19","author":"Neville","year":"1996","journal-title":"J Immunother"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1158","DOI":"10.1016\/s0041-1345(96)00503-9","article-title":"Mechanisms of tolerance induced by an lmmunotoxin against CD~E in a rhesus kidney allograft model","volume":"1","author":"Fechner","year":"1997","journal-title":"Transplantation Proceedings"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1097\/00007890-199909270-00019","article-title":"In vivo T cell depletion in miniature swine using the swine CD3 immunotoxin, pCD3-CRM91","volume":"68","author":"Huang","year":"1999","journal-title":"Transplantation"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1172\/JCI8721","article-title":"Mixed chimerism and tolerance without whole body irradiation in a large animal model","volume":"105","author":"Fuchimoto","year":"2000","journal-title":"J Clin Invest"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1097\/01.tp.0000226061.59196.84","article-title":"Stable multilineage chimerism without graft versus host disease following nonmyeloablative haploidentical hematopoietic cell transplantation","volume":"81","author":"Cina","year":"2006","journal-title":"Transplantation"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1021\/bc0603438","article-title":"Improvement of a recombinant anti-monkey anti-CD3 diphtheria toxin based immunotoxin by yeast display affinity maturation of the scFv","volume":"18","author":"Wang","year":"2007","journal-title":"Bioconjugate Chem"},{"key":"B29","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1111\/ajt.13952","article-title":"Tolerance of vascularized islet-kidney transplants in rhesus monkeys","volume":"17","author":"Pathiraja","year":"2017","journal-title":"Am J Transplant"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.612737","article-title":"Tregs and mixed chimerism as approaches for tolerance induction in islet transplantation","volume":"11","author":"Pathak","year":"2021","journal-title":"Front Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.693105","article-title":"The yin and yang of type 1 regulatory T cells: From discovery to clinical application","volume":"12","author":"Sayitoglu","year":"2021","journal-title":"Front Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00596","article-title":"Alloreactive regulatory T cells allow the generation of mixed chimerism and transplant tolerance","volume":"6","author":"Ruiz","year":"2015","journal-title":"Front Immunol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1038\/nm1688","article-title":"Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes","volume":"14","author":"Joffre","year":"2008","journal-title":"Nat Med"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.trim.2013.10.004","article-title":"Recombinant anti-monkey CD3 immunotoxin depletes peripheral lymph node T lymphocytes more effectively than rabbit anti-thymocyte globulin in na\u00efve baboons","volume":"29","author":"Wamala","year":"2013","journal-title":"Transplant Immunol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"279ra39","DOI":"10.1126\/scitranslmed.3010302","article-title":"Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells","volume":"7","author":"Watanabe","year":"2015","journal-title":"Sci Transl Med"},{"key":"B36","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/S0039-6060(98)70151-5","article-title":"Primate renal transplants using immunotoxin","volume":"124","author":"Knechtle","year":"1998","journal-title":"Surgery"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/00007890-199701150-00002","article-title":"FN18-Crm9 immunotoxin promotes tolerance in primate renal Allografts1","volume":"63","author":"Knechtle","year":"1997","journal-title":"Transplantation"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.9.5753","article-title":"Metastable tolerance to rhesus monkey renal transplants is correlated with allograft TGF-\u03b21 + CD4 + T regulatory cell infiltrates","volume":"172","author":"Torrealba","year":"2004","journal-title":"J Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1097\/01.TP.0000075788.72614.D4","article-title":"Immunotoxin-treated rhesus monkeys: A model for renal allograft chronic rejection1","volume":"76","author":"Torrealba","year":"2003","journal-title":"Transplantation"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-6143.2012.04074.x","article-title":"Enhanced De novo alloantibody and antibody-mediated injury in rhesus macaques","volume":"12","author":"Page","year":"2012","journal-title":"Am J Transplant"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-019-0203-7","article-title":"The pursuit of transplantation tolerance: New mechanistic insights","volume":"16","author":"Gupta","year":"2019","journal-title":"Cell Mol Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0400084101","article-title":"Donor-specific transplantation tolerance: The paradoxical behavior of CD4+CD25+ T cells","volume":"101","author":"Graca","year":"2004","journal-title":"Proc Natl Acad Sci"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2017.07.008","article-title":"Mechanisms of mixed chimerism-based transplant tolerance","volume":"38","author":"Zuber","year":"2017","journal-title":"Trends Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2012.08.004","article-title":"Lack of antidonor alloantibody does not indicate lack of immune sensitization: Studies of graft loss in a haploidentical hematopoietic cell transplantation swine model","volume":"18","author":"Duran-Struuck","year":"2012","journal-title":"Biol Blood Marrow Transplant"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-042617-053214","article-title":"Tissue-resident T cells and other resident leukocytes","volume":"37","author":"Masopust","year":"2019","journal-title":"Annu Rev Immunol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines10061221","article-title":"Comparison of CD3e antibody and CD3e-sZAP immunotoxin treatment in mice identifies sZAP as the main driver of vascular leakage","volume":"10","author":"Kim","year":"2022","journal-title":"Biomedicines"},{"key":"B47","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":"B48","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abb4582","article-title":"Measurement of leukocyte trafficking kinetics in macaques by serial intravascular staining","volume":"13","author":"Potter","year":"2021","journal-title":"Sci Trans Med"},{"key":"B49","doi-asserted-by":"publisher","first-page":"6993","DOI":"10.4049\/jimmunol.174.11.6993","article-title":"Lymph node occupancy is required for the peripheral development of alloantigen-specific Foxp3+ regulatory T cells","volume":"174","author":"Ochando","year":"2005","journal-title":"J Immunol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20061405","article-title":"CCR7 is required for the in vivo function of CD4+ CD25+ regulatory T cells","volume":"204","author":"Schneider","year":"2007","journal-title":"J Exp Med"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2008.12.022","article-title":"Regulatory T cells sequentially migrate from inflamed tissues to draining lymph nodes to suppress the alloimmune response","volume":"30","author":"Zhang","year":"2009","journal-title":"Immunity"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20081359","article-title":"Antigen-specific peripheral shaping of the natural regulatory T cell population","volume":"205","author":"Lathrop","year":"2008","journal-title":"J Exp Med"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20130604","article-title":"Follicular regulatory T cells control humoral autoimmunity via NFAT2-regulated CXCR5 expression","volume":"211","author":"Vaeth","year":"2014","journal-title":"J Exp Med"},{"key":"B54","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":"B55","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-01-0177","article-title":"Regulatory T-cell compartmentalization and trafficking","volume":"108","author":"Wei","year":"2006","journal-title":"Blood"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1097\/TP.0b013e318237d6d4","article-title":"Tolerance to vascularized composite allografts in canine mixed hematopoietic chimeras","volume":"92","author":"Mathes","year":"2011","journal-title":"Transplantation"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1097\/01.tp.0000250937.46187.ca","article-title":"Isolation of regulatory T cells in the skin of a human hand-allograft, up to six years posttransplantation","volume":"82","author":"Eljaafari","year":"2006","journal-title":"Transplantation"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V96.3.1157","article-title":"Molecular modification of a recombinant anti-CD3\u03f5-directed immunotoxin by inducing terminal cysteine bridging enhances anti-GVHD efficacy and reduces organ toxicity in a lethal murine model","volume":"96","author":"Vallera","year":"2000","journal-title":"Blood"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V86.11.4367.bloodjournal86114367","article-title":"Therapy for ongoing graft-versus-host disease induced across the major or minor histocompatibility barrier in mice with anti-CD3F(ab\u2019)2-ricin toxin a chain immunotoxin","volume":"86","author":"Vallera","year":"1995","journal-title":"Blood"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/gzm040","article-title":"A fold-back single-chain diabody format enhances the bioactivity of an anti-monkey CD3 recombinant diphtheria toxin-based immunotoxin","volume":"20","author":"Kim","year":"2007","journal-title":"Protein Eng Design Selection"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/10.9.1071","article-title":"Renal dysfunction accounts for the dose limiting toxicity of DT390anti- CD3sFv, a potential new recombinant anti-GVHD immunotoxin","volume":"10","author":"Vallera","year":"1997","journal-title":"Protein Eng Design Selection"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V95.7.2321","article-title":"A novel nuclear phosphoprotein, GANP, is up-regulated in centrocytes of the germinal center and associated with MCM3, a protein essential for DNA replication","volume":"95","author":"Kuwahara","year":"2000","journal-title":"Blood"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.70.4.578","article-title":"Spontaneous formation of germinal centers in autoimmune mice","volume":"70","author":"Luzina","year":"2001","journal-title":"J Leukocyte Biol"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(01)00177-7","article-title":"The AIDS disease of CD4C\/HIV transgenic mice shows impaired germinal centers and autoantibodies and develops in the absence of IFN-\u03b3 and IL-6","volume":"15","author":"Poudrier","year":"2001","journal-title":"Immunity"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1600883","article-title":"Water-in-Oil\u2013only adjuvants selectively promote T follicular helper cell polarization through a type I IFN and IL-6\u2013dependent pathway","volume":"197","author":"Riteau","year":"2016","journal-title":"JI"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1809329116","article-title":"Pivotal role for \u03b1 V integrins in sustained tfh support of the germinal center response for long-lived plasma cell generation","volume":"116","author":"Schrock","year":"2019","journal-title":"Proc Natl Acad Sci USA"},{"key":"B67","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/j.immuni.2018.01.015","article-title":"T Cells in nonlymphoid tissues give rise to lymph-Node-Resident memory T cells","volume":"48","author":"Beura","year":"2018","journal-title":"Immunity"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2013.00245","article-title":"Treg inducing adjuvants for therapeutic vaccination against chronic inflammatory diseases","volume":"4","author":"Keijzer","year":"2013","journal-title":"Front Immunol"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1016\/j.trim.2012.05.001","article-title":"Immunosuppressive drugs on inducing Ag-specific CD4+CD25+Foxp3+ treg cells during immune response in vivo","volume":"27","author":"Wu","year":"2012","journal-title":"Transplant Immunol"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1038\/nature17655","article-title":"Normalizing the environment recapitulates adult human immune traits in laboratory mice","volume":"532","author":"Beura","year":"2016","journal-title":"Nature"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1084\/jem.177.3.707","article-title":"Regulation of thymocyte development through CD3. i. timepoint of ligation of CD3 epsilon determines clonal deletion or induction of developmental program","volume":"177","author":"Levelt","year":"1993","journal-title":"J Exp Med"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2010.10","article-title":"Tonic ubiquitylation controls T-cell receptor:CD3 complex expression during T-cell development","volume":"29","author":"Wang","year":"2010","journal-title":"EMBO J"},{"key":"B73","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1038\/nri821","article-title":"CD4+CD25+ suppressor T cells: more questions than answers","volume":"2","author":"Shevach","year":"2002","journal-title":"Nat Rev Immunol"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1038\/ni1178","article-title":"Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self","volume":"6","author":"Sakaguchi","year":"2005","journal-title":"Nat Immunol"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-04-1987","article-title":"Bone marrow is a reservoir for CD4 + CD25 + regulatory T cells that traffic through CXCL12\/CXCR4 signals","volume":"64","author":"Zou","year":"2004","journal-title":"Cancer Res"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1002\/1521-4141(200104)31:4<1247::AID-IMMU1247>3.0.CO;2-M","article-title":"Human CD4+CD25+ thymocytes and peripheral T cells have immune suppressive activity in vitro","volume":"31","author":"Stephens","year":"2001","journal-title":"Eur J Immunol"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1038\/nm1093","article-title":"Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival","volume":"10","author":"Curiel","year":"2004","journal-title":"Nat Med"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.1A0715-296R","article-title":"Lymph node trafficking of regulatory T cells is prerequisite for immune suppression","volume":"99","author":"Huang","year":"2016","journal-title":"J Leukocyte Biol"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2009.03217.x","article-title":"Rosenzweig m. partial and transient modulation of the CD3-t-cell receptor complex, elicited by low-dose regimens of monoclonal anti-CD3, is sufficient to induce disease remission in non-obese diabetic mice","volume":"130","author":"Mehta","year":"2010","journal-title":"Immunology"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(78)90099-5","article-title":"One molecule of diphtheria toxin fragment a introduced into a cell can kill the cell","volume":"15","author":"Yamaizumi","year":"1978","journal-title":"Cell"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1038\/nri2916","article-title":"Phenotypical and functional specialization of FOXP3+ regulatory T cells","volume":"11","author":"Campbell","year":"2011","journal-title":"Nat Rev Immunol"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20030686","article-title":"Continuous activation of autoreactive CD4+ CD25+ regulatory T cells in the steady state","volume":"198","author":"Fisson","year":"2003","journal-title":"J Exp Med"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.164.1.183","article-title":"Suppressor effector function of CD4 + CD25 + immunoregulatory T cells is antigen nonspecific","volume":"164","author":"Thornton","year":"2000","journal-title":"J Immunol"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.5.2461","article-title":"The subpopulation of CD4 + CD25 + splenocytes that delays adoptive transfer of diabetes expresses l-selectin and high levels of CCR7","volume":"169","author":"Szanya","year":"2002","journal-title":"J Immunol"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-05-2044","article-title":"Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD","volume":"105","author":"Ermann","year":"2005","journal-title":"Blood"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-05-1850","article-title":"L-selectinhi but not the l-selectinlo CD4+25+ T-regulatory cells are potent inhibitors of GVHD and BM graft rejection","volume":"104","author":"Taylor","year":"2004","journal-title":"Blood"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.7.4407","article-title":"Perturbed homeostasis of peripheral T cells elicits decreased susceptibility to anti-CD3-Induced apoptosis in prediabetic nonobese diabetic mice","volume":"173","author":"Yang","year":"2004","journal-title":"J Immunol"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.8.4525","article-title":"Treatment with nonmitogenic anti-CD3 monoclonal antibody induces CD4 + T cell unresponsiveness and functional reversal of established experimental autoimmune encephalomyelitis","volume":"174","author":"Kohm","year":"2005","journal-title":"J Immunol"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.2.933","article-title":"Nonmitogenic CD3 antibody reverses virally induced (Rat insulin promoter-lymphocytic choriomeningitis virus) autoimmune diabetes without impeding viral clearance","volume":"168","author":"von Herrath","year":"2002","journal-title":"J Immunol"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.2337\/db08-1432","article-title":"Rapamycin prevents and breaks the Anti-CD3\u2013induced tolerance in NOD mice","volume":"58","author":"Valle","year":"2009","journal-title":"Diabetes"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1038\/nm924","article-title":"TGF-\u03b2-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes","volume":"9","author":"Belghith","year":"2003","journal-title":"Nat Med"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00218","article-title":"The induction and maintenance of transplant tolerance engages both regulatory and anergic CD4+ T cells","volume":"8","author":"Besan\u00e7on","year":"2017","journal-title":"Front Immunol"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100713","article-title":"Anti-CD3 therapy promotes tolerance by selectively depleting pathogenic cells while preserving regulatory T cells","volume":"187","author":"Penaranda","year":"2011","journal-title":"JI"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-05-217315","article-title":"Anti-CD3 antibodies modulate anti\u2013factor VIII immune responses in hemophilia a mice after factor VIII plasmid-mediated gene therapy","volume":"114","author":"Peng","year":"2009","journal-title":"Blood"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01103","article-title":"Intestinal delivery of proinsulin and IL-10 via lactococcus lactis combined with low-dose anti-CD3 restores tolerance outside the window of acute type 1 diabetes diagnosis","volume":"11","author":"Cook","year":"2020","journal-title":"Front Immunol"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(02)00367-9","article-title":"CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-Deficient mice: Implications for the nonredundant function of IL-2","volume":"17","author":"Malek","year":"2002","journal-title":"Immunity"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.9.4850","article-title":"Homeostasis of peripheral CD4 + T cells: IL-2R\u03b1 and IL-2 shape a population of regulatory cells that controls CD4 + T cell numbers","volume":"169","author":"Almeida","year":"2002","journal-title":"J Immunol"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1038\/nm1312","article-title":"Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells","volume":"11","author":"Zhang","year":"2005","journal-title":"Nat Med"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.10.012","article-title":"Continuous T cell receptor signals maintain a functional regulatory T cell pool","volume":"41","author":"Vahl","year":"2014","journal-title":"Immunity"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3004","article-title":"Continuous requirement for the TCR in regulatory T cell function","volume":"15","author":"Levine","year":"2014","journal-title":"Nat Immunol"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1402384","article-title":"Regulatory T cells require TCR signaling for their suppressive function","volume":"194","author":"Schmidt","year":"2015","journal-title":"JI"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a015511","article-title":"Lymphodepletional strategies in transplantation","volume":"3","author":"Page","year":"2013","journal-title":"Cold Spring Harb Perspect Med"},{"key":"B103","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s12865-019-0308-x","article-title":"Increased circulating tfh to tfr ratio in chronic renal allograft dysfunction: a pilot study","volume":"20","author":"Yan","year":"2019","journal-title":"BMC Immunol"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01972","article-title":"Immunosuppression has long-lasting effects on circulating follicular regulatory T cells in kidney transplant recipients","volume":"11","author":"Niu","year":"2020","journal-title":"Front Immunol"},{"key":"B105","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/0005-2736(93)90115-G","article-title":"Subcutaneous administration of liposomes: A comparison with the intravenous and intraperitoneal routes of injection","volume":"1150","author":"Allen","year":"1993","journal-title":"Biochim Biophys Acta (BBA) - Biomembranes"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1515\/ejnm-2015-0003","article-title":"Passive and specific targeting of lymph nodes: the influence of the administration route","volume":"7","author":"Pitorre","year":"2015","journal-title":"Eur J Nanomed"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.04952-14","article-title":"Mass spectrometry imaging reveals heterogeneous efavirenz distribution within putative HIV reservoirs","volume":"59","author":"Thompson","year":"2015","journal-title":"Antimicrob Agents Chemother"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.b.20496","article-title":"Variability of CD3 membrane expression and T cell activation capacity","author":"El Hentati","year":"2010","journal-title":"Cytometry Part B: Clin Cytometry"},{"key":"B109","doi-asserted-by":"publisher","first-page":"117ra7","DOI":"10.1126\/scitranslmed.3003008","article-title":"Skin effector memory T cells do not recirculate and provide immune protection in alemtuzumab-treated CTCL patients","volume":"4","author":"Clark","year":"2012","journal-title":"Sci Transl Med"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.2174\/1566524018666181004120112","article-title":"Probable mechanisms involved in immunotoxin mediated capillary leak syndrome (CLS) and recently developed countering strategies","volume":"18","author":"Darvishi","year":"2018","journal-title":"Curr Mol Med"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.1038\/nbt800","article-title":"Genetic engineering of an immunotoxin to eliminate pulmonary vascular leak in mice","volume":"21","author":"Smallshaw","year":"2003","journal-title":"Nat Biotechnol"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-08-173195","article-title":"A protease-resistant immunotoxin against CD22 with greatly increased activity against CLL and diminished animal toxicity","volume":"113","author":"Weldon","year":"2009","journal-title":"Blood"},{"key":"B113","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1158\/1535-7163.MCT-12-0336","article-title":"A recombinant immunotoxin against the tumor-associated antigen mesothelin reengineered for high activity, low off-target toxicity, and reduced antigenicity","volume":"12","author":"Weldon","year":"2013","journal-title":"Mol Cancer Ther"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-007-0321-4","article-title":"Treatment of hepatocellular carcinoma in a mouse xenograft model with an immunotoxin which is engineered to eliminate vascular leak syndrome","volume":"56","author":"Wang","year":"2007","journal-title":"Cancer Immunol Immunother"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.7.3957","article-title":"Evidence for a structural motif in toxins and interleukin-2 that may be responsible for binding to endothelial cells and initiating vascular leak syndrome","volume":"96","author":"Baluna","year":"1999","journal-title":"Proc Natl Acad Sci"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.1002\/smll.201800665","article-title":"Selective CXCR4+ cancer cell targeting and potent antineoplastic effect by a nanostructured version of recombinant ricin","volume":"14","author":"D\u00edaz","year":"2018","journal-title":"Small"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1815087116","article-title":"Second-generation IL-2 receptor-targeted diphtheria fusion toxin exhibits antitumor activity and synergy with anti\u2013PD-1 in melanoma","volume":"116","author":"Cheung","year":"2019","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B118","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1201682","article-title":"Cutting edge: Intravascular staining redefines lung CD8 T cell responses","volume":"189","author":"Anderson","year":"2012","journal-title":"J Immunol"},{"key":"B119","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0150606","article-title":"A protocol for the comprehensive flow cytometric analysis of immune cells in normal and inflamed murine non-lymphoid tissues","volume":"11","author":"Yu","year":"2016","journal-title":"PloS One"},{"key":"B120","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2013-0086MA","article-title":"Flow cytometric analysis of macrophages and dendritic cell subsets in the mouse lung","volume":"49","author":"Misharin","year":"2013","journal-title":"Am J Respir Cell Mol Biol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1011190\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T05:07:46Z","timestamp":1666760866000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1011190\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,26]]},"references-count":120,"alternative-id":["10.3389\/fimmu.2022.1011190"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.1011190","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.07.25.501205","asserted-by":"object"}]},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,26]]},"article-number":"1011190"}}