title: Heterogeneous CD3 expression levels in differing T cell subsets correlate with the in vivo anti-CD3-mediated T cell modulation.
abstract: The tolerogenic anti-CD3ε monoclonal Abs (anti-CD3) are promising compounds for the treatment of type 1 diabetes. Anti-CD3 administration induces transient T cell depletion both in preclinical and in clinical studies. Notably, the said depletion mainly affects CD4(+) but not CD8(+) T cells. Moreover, type 1 diabetes reversal in preclinical models is accompanied by the selective expansion of CD4(+)Foxp3(+) T regulatory (Treg) cells, which are fundamental for the long-term maintenance of anti-CD3-mediated tolerance. The mechanisms that lead to this immune-shaping by affecting mainly CD4(+) T effector cells while sparing CD4(+)Foxp3(+) Treg cells have still to be fully elucidated. This study shows that CD3 expression levels differ from one T cell subset to another. CD4(+)Foxp3(-) T cells contain higher amounts of CD3 molecules than do CD4(+)Foxp3(+) and CD8(+) T cells in both mice and humans. The said differences correlate with the anti-CD3-mediated immune resetting that occurs in vivo after anti-CD3 administration in diabetic NOD mice. Additionally, transcriptome analysis demonstrates that CD4(+)Foxp3(+) Treg cells are significantly less responsive than are CD4(+)Foxp3(-) T cells to anti-CD3 treatment at a molecular level. Thus, heterogeneity in CD3 expression seems to confer to the various T cell subsets differing susceptibility to the in vivo tolerogenic anti-CD3-mediated modulation. These data shed new light on the molecular mechanism that underlies anti-CD3-mediated immune resetting and thus may open new opportunities to improve this promising treatment.
authors: San Raffaele Diabetes Research Institute, San Raffaele Scientific Institute, 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy;
authors: Andrea
authors: A
authors: Valle
authors: San Raffaele Diabetes Research Institute, San Raffaele Scientific Institute, 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy;
authors: Giulia
authors: G
authors: Barbagiovanni
authors: San Raffaele Diabetes Research Institute, San Raffaele Scientific Institute, 20132 Milan, Italy;
authors: Tatiana
authors: T
authors: Jofra
authors: San Raffaele Diabetes Research Institute, San Raffaele Scientific Institute, 20132 Milan, Italy;
authors: Angela
authors: A
authors: Stabilini
authors: Université Pierre et Marie Curie Université Paris 06, 75005 Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7211, 75013 Paris, France; INSERM Unité 959, Immunology-Immunopathology-Immunotherapy, 75013 Paris, France; INSERM Unité 932, 75005 Paris, France; Institut Curie, Section Recherche, 75005 Paris, France;
authors: Louis
authors: L
authors: Perol
authors: Université Pierre et Marie Curie Université Paris 06, 75005 Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7211, 75013 Paris, France; INSERM Unité 959, Immunology-Immunopathology-Immunotherapy, 75013 Paris, France;
authors: Audrey
authors: A
authors: Baeyens
authors: San Raffaele Diabetes Research Institute, San Raffaele Scientific Institute, 20132 Milan, Italy; Department of Science and Technology, University of Sannio, 82100 Benevento, Italy;
authors: Santosh
authors: S
authors: Anand
authors: INSERM Unité 580, 75015 Paris, France; Bioinformatics Platform, Faculty of Medicine Paris Descartes, Necker Hospital for Sick Children, 75015 Paris, France;
authors: Nicolas
authors: N
authors: Cagnard
authors: San Raffaele Diabetes Research Institute, San Raffaele Scientific Institute, 20132 Milan, Italy;
authors: Nicola
authors: N
authors: Gagliani
authors: Université Pierre et Marie Curie Université Paris 06, 75005 Paris, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7211, 75013 Paris, France; INSERM Unité 959, Immunology-Immunopathology-Immunotherapy, 75013 Paris, France; INSERM Unité 932, 75005 Paris, France; Institut Curie, Section Recherche, 75005 Paris, France; INSERM Center of Clinical Investigation (CBT507 IGR-Curie), 75005 Paris, France; and.
authors: Eliane
authors: E
authors: Piaggio
authors: San Raffaele Diabetes Research Institute, San Raffaele Scientific Institute, 20132 Milan, Italy; TrialNet Clinical Center, San Raffaele Hospital, 20132 Milan, Italy battaglia.manuela@hsr.it.
authors: Manuela
authors: M
authors: Battaglia
mesh_terms: D000293:Adolescent; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000494:pharmacology*; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D018740:Genetic Heterogeneity; D006801:Humans; D007004:Hypoglycemic Agents / Q000276:immunology / Q000494:pharmacology*; D007108:Immune Tolerance / Q000187:drug effects; D007155:Immunologic Factors / Q000494:pharmacology*; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D017252:CD3 Complex; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007004:Hypoglycemic Agents; D007155:Immunologic Factors; C456519:visilizumab