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.
MeSH terms
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Animals
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Annexin A5 / metabolism
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Antigen Presentation / immunology
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Antigens, CD / metabolism
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Antigens, Differentiation, T-Lymphocyte / metabolism
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Apoptosis / drug effects
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Apoptosis Regulatory Proteins
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B-Lymphocytes / immunology
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B-Lymphocytes / radiation effects
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B-Lymphocytes / virology
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B7-1 Antigen / metabolism
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B7-2 Antigen
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CD28 Antigens / metabolism
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / drug effects*
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CD4-Positive T-Lymphocytes / metabolism
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Carrier Proteins / genetics
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Cattle
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Cell Cycle / drug effects
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Child, Preschool
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Clone Cells / drug effects
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Clone Cells / immunology
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Clone Cells / metabolism
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Coculture Techniques
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Cytokines / metabolism*
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DNA-Binding Proteins / genetics
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Endosomal Sorting Complexes Required for Transport
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Flow Cytometry
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Gene Expression / drug effects
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Herpesvirus 4, Human / growth & development
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Humans
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Immunosuppressive Agents / immunology
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Immunosuppressive Agents / pharmacology
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Interferon-gamma / metabolism
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Interleukin-10 / metabolism
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Interleukin-10 / pharmacology
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Interleukin-2 / metabolism
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Interleukin-4 / metabolism
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Intracellular Signaling Peptides and Proteins*
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Lectins, C-Type
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Lymphocyte Activation / drug effects*
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Lymphocyte Activation / immunology
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Membrane Glycoproteins / metabolism
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Milk Hypersensitivity / immunology
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Milk Proteins / pharmacology
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Mitochondrial Proteins / genetics
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Peptide Fragments / pharmacology
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Phosphoproteins / genetics
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Protein Precursors / pharmacology
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Protein Serine-Threonine Kinases
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RNA, Messenger / drug effects
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Interleukin-2 / metabolism
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Receptors, Transforming Growth Factor beta / genetics
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Serine Endopeptidases / genetics
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Smad7 Protein
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Trans-Activators / genetics
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Transforming Growth Factor beta / pharmacology*
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Transforming Growth Factor beta / physiology
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Transforming Growth Factor beta1
Substances
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Annexin A5
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Antigens, CD
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Antigens, Differentiation, T-Lymphocyte
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Apoptosis Regulatory Proteins
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B7-1 Antigen
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B7-2 Antigen
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CD28 Antigens
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CD69 antigen
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CD86 protein, human
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Carrier Proteins
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Cytokines
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DIABLO protein, human
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DNA-Binding Proteins
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Endosomal Sorting Complexes Required for Transport
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Immunosuppressive Agents
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Interleukin-2
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Intracellular Signaling Peptides and Proteins
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Lectins, C-Type
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Membrane Glycoproteins
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Milk Proteins
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Mitochondrial Proteins
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Peptide Fragments
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Phosphoproteins
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Protein Precursors
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RNA, Messenger
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Receptors, Interleukin-2
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Receptors, Transforming Growth Factor beta
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SMAD7 protein, human
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Smad7 Protein
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Trans-Activators
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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hepatocyte growth factor-regulated tyrosine kinase substrate
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Interleukin-10
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Interleukin-4
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Interferon-gamma
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type II
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ZFYVE16 protein, human
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Serine Endopeptidases