title: Transforming growth factor-beta inhibits human antigen-specific CD4+ T cell proliferation without modulating the cytokine response.
abstract: Transforming growth factor (TGF)-beta has been demonstrated to play a key role in the regulation of the immune response, mainly by its suppressive function towards cells of the immune system. In humans, the effect of TGF-beta on antigen-specific established memory T cells has not been investigated yet. In this study antigen-specific CD4(+) T cell clones (TCC) were used to determine the effect of TGF-beta on antigen-specific proliferation, the activation status of the T cells and their cytokine production. This study demonstrates that TGF-beta is an adequate suppressor of antigen-specific T cell proliferation, by reducing the cell-cycle rate rather than induction of apoptosis. Addition of TGF-beta resulted in increased CD69 expression and decreased CD25 expression on T cells, indicating that TGF-beta is able to modulate the activation status of in vivo differentiated T cells. On the contrary, the antigen-specific cytokine production was not affected by TGF-beta. Although TGF-beta was suppressive towards the majority of the T cells, insensitivity of a few TCC towards TGF-beta was also observed. This could not be correlated to differential expression of TGF-beta signaling molecules such as Smad3, Smad7, SARA (Smad anchor for receptor activation) and Hgs (hepatocyte growth factor-regulated tyrosine kinase substrate). In summary, TGF-beta has a pronounced inhibitory effect on antigen-specific T cell proliferation without modulating their cytokine production.
authors.affiliation: Department of Dermatology/Allergology, University Medical Center, PO Box 85.500, 3508 GA Utrecht, The Netherlands. m.tiemessen@azu.nl
authors.forename: Machteld M
authors.initials: MM
authors.lastname: Tiemessen
authors.forename: Steffen
authors.initials: S
authors.lastname: Kunzmann
authors.forename: Carsten B
authors.initials: CB
authors.lastname: Schmidt-Weber
authors.forename: Johan
authors.initials: J
authors.lastname: Garssen
authors.forename: Carla A F M
authors.initials: CA
authors.lastname: Bruijnzeel-Koomen
authors.forename: Edward F
authors.initials: EF
authors.lastname: Knol
authors.forename: Els
authors.initials: E
authors.lastname: van Hoffen
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017951:Antigen Presentation / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D001402:B-Lymphocytes / Q000276:immunology / Q000528:radiation effects / Q000821:virology; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D002417:Cattle; D002453:Cell Cycle / Q000187:drug effects; D002675:Child, Preschool; D002999:Clone Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics; D056827:Endosomal Sorting Complexes Required for Transport; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000254:growth & development; D006801:Humans; D007166:Immunosuppressive Agents / Q000276:immunology / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism / Q000494:pharmacology; D007376:Interleukin-2 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D008562:Membrane Glycoproteins / Q000378:metabolism; D016269:Milk Hypersensitivity / Q000276:immunology; D008894:Milk Proteins / Q000494:pharmacology; D024101:Mitochondrial Proteins / Q000235:genetics; D010446:Peptide Fragments / Q000494:pharmacology; D010750:Phosphoproteins / Q000235:genetics; D011498:Protein Precursors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics; D051906:Smad7 Protein; D015534:Trans-Activators / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology* / Q000502:physiology; D053773:Transforming Growth Factor beta1; D000099192:CD69 Antigens
chemical_list: D017304:Annexin A5; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D002352:Carrier Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D007166:Immunosuppressive Agents; D007371:Interferon-gamma; D016753:Interleukin-10; D007376:Interleukin-2; D015847:Interleukin-4; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D008894:Milk Proteins; D024101:Mitochondrial Proteins; D010446:Peptide Fragments; D010750:Phosphoproteins; D011498:Protein Precursors; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D000077294:Receptor, Transforming Growth Factor-beta Type II; D015375:Receptors, Interleukin-2; D018125:Receptors, Transforming Growth Factor beta; D012697:Serine Endopeptidases; D051906:Smad7 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000099192:CD69 Antigens; C497964:CD86 protein, human; C412403:DIABLO protein, human; C497806:SMAD7 protein, human; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; C116420:ZFYVE16 protein, human