Phenotype, localization, and mechanism of suppression of CD4(+)CD25(+) human thymocytes.
Phenotypic markers, localization, functional activities, and mechanisms of action in vitro of CD4(+)CD25(+) T cells, purified from postnatal human thymuses, were investigated. These cells showed poor or no proliferation in mixed lymphocyte culture (MLC), and suppressed in a dose-dependent fashion the proliferative response to allogeneic stimulation of CD4(+)CD25(-) thymocytes. Virtually all CD4(+)CD25(+) thymocytes constitutively expressed cytoplasmic T lymphocyte antigen (CTLA)-4, surface tumor necrosis factor type 2 receptor (TNFR2), and CCR8. They prevalently localized to perivascular areas of fibrous septa and responded to the chemoattractant activity of CCL1/I-309, which was found to be produced by either thymic medullary macrophages or fibrous septa epithelial cells. After polyclonal activation, CD4(+)CD25(+) thymocytes did not produce the cytokines interleukin (IL)-2, IL-4, IL-5, IL-13, interferon gamma, and only a very few produced IL-10, but all they expressed on their surface CTLA-4 and the majority of them also transforming growth factor (TGF)-beta1. The suppressive activity of these cells was contact dependent and associated with the lack of IL-2 receptor (IL-2R) alpha-chain (CD25) expression in target cells. Such a suppressive activity was partially inhibited by either anti-CTLA-4 or anti-TGF-beta1, and was completely blocked by a mixture of these monoclonal antibodies, which were also able to restore in target T cells the expression of IL-2R alpha-chain and, therefore, their responsiveness to IL-2. These data demonstrate that CD4(+)CD25(+) human thymocytes represent a population of regulatory cells that migrate in response to the chemokine CCL1/I-309 and exert their suppressive function via the inhibition of IL-2R alpha-chain in target T cells, induced by the combined activity of CTLA-4 and membrane TGF-beta1.
Annunziato
Francesco
F
Department of Internal Medicine, University Florence, Italy.
Cosmi
Lorenzo
L
Liotta
Francesco
F
Lazzeri
Elena
E
Manetti
Roberto
R
Vanini
Vittorio
V
Romagnani
Paola
P
Maggi
Enrico
E
Romagnani
Sergio
S
D000069594:Abatacept; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology; D015704:CD4 Antigens / Q000032:analysis*; D060908:CTLA-4 Antigen; D002675:Child, Preschool; D006801:Humans; D018796:Immunoconjugates; D016130:Immunophenotyping; D007223:Infant; D007231:Infant, Newborn; D007376:Interleukin-2 / Q000494:pharmacology; D054401:Receptors, CCR8; D019707:Receptors, Chemokine / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000032:analysis*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000502:physiology; D053773:Transforming Growth Factor beta1
D015703:Antigens, CD; D000943:Antigens, Differentiation; C103330:CCR8 protein, human; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D007376:Interleukin-2; D054401:Receptors, CCR8; D019707:Receptors, Chemokine; D015375:Receptors, Interleukin-2; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000069594:Abatacept