title: A novel costimulation pathway via the 4C8 antigen for the induction of CD4+ regulatory T cells.
abstract: CD4(+)CD25(+) regulatory T (Treg) cells naturally occur in mice and humans, and similar Treg cells can be induced in vivo and in vitro. However, the molecular mechanisms that mediate the generation of these Treg cell populations remain unknown. We previously described anti-4C8 mAbs that inhibit the postadhesive transendothelial migration of T cells through human endothelial cell monolayers. We demonstrate in this work that Treg cells are induced by costimulation of CD4(+) T cells with anti-CD3 plus anti-4C8. The costimulation induced full activation of CD4(+) T cells with high levels of IL-2 production and cellular expansion that were comparable to those obtained on costimulation by CD28. However, upon restimulation, 4C8-costimulated cells produced high levels of IL-10 but no IL-2 or IL-4, and maintained high expression levels of CD25 and intracellular CD152, as compared to CD28-costimulated cells. The former cells showed hyporesponsiveness to anti-CD3 stimulation and suppressed the activation of bystander T cells depending on cell contact but not IL-10 or TGF-beta. The suppressor cells developed from CD4(+)CD25(-)CD45RO(+) cells. The results suggest that 4C8 costimulation induces the generation of Treg cells that share phenotypic and functional features with CD4(+)CD25(+) T cells, and that CD25(-) memory T cells may differentiate into certain Treg cell subsets in the periphery.
authors.affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical School, Tochigi, Japan. jmas@jichi.ac.jp
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Masuyama
authors.forename: Shuji
authors.initials: S
authors.lastname: Kaga
authors.forename: Shogo
authors.initials: S
authors.lastname: Kano
authors.forename: Seiji
authors.initials: S
authors.lastname: Minota
mesh_terms: D000069594:Abatacept; D000328:Adult; D015703:Antigens, CD / Q000502:physiology*; D000943:Antigens, Differentiation / Q000096:biosynthesis; D024201:Bystander Effect / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D060908:CTLA-4 Antigen; D002448:Cell Adhesion / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002474:Cell-Free System / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D018796:Immunoconjugates; D016753:Interleukin-10 / Q000502:physiology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D016853:Muromonab-CD3 / Q000494:pharmacology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: C465395:4C8 antigen, human; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D016207:Cytokines; D018796:Immunoconjugates; D007376:Interleukin-2; D016853:Muromonab-CD3; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D000069594:Abatacept