Regulation of cytokine production by human Th0 cells following stimulation with peptide analogues: differential expression of TGF-beta in activation and anergy.
The different biological activities of T-cell-derived cytokines and their level of production influences the qualitative nature of immune responses and, in certain forms of T-cell tolerance, the lack of antigen responsiveness is associated with the production of transforming growth factor-beta (TGF-beta) and interleukin-4 (IL-4). In this study we have investigated the effects of T-cell receptor (TCR) ligation with peptide analogues and the native peptide, in the presence and absence of costimulation, on cytokine production by human T-helper type 0 (Th0) cells reactive with influenza virus haemagglutinin (HA) peptide (HA306-318) and restricted by HLA-DRB1*0101. We observed that resting Th0 cells constitutively produced TGF-beta, but when stimulated with peptide and antigen-presenting cells (APC) under conditions that induce clonal expansion, TGF-beta secretion was abrogated. Furthermore, exposure of the T cells to the wild-type HA peptide under conditions that induce T-cell anergy resulted in the secretion of TGF-beta, and subsequent antigenic rechallenge was unable to override this signal and down-regulate TGF-beta production. Stimulation with altered TCR ligands that failed to induce proliferation also resulted in marked production of TGF-beta, although in many instances the levels were less than those observed in the total absence of antigen, suggesting that partial signalling has occurred. Although in general, there was a direct positive correlation between proliferation and the production of IL-2, IL-4 and interferon-gamma (IFN-gamma) following stimulation with certain analogues, the production of selected cytokines was dissociated.
Tsitoura
D C
DC
Department of Biology, Imperial College of Science, Technology and Medicine, King's College School of Medicine and Dentistry, London, UK.
Gelder
C M
CM
Kemeny
D M
DM
Lamb
J R
JR
D000595:Amino Acid Sequence; D018929:Cell Culture Techniques; D002455:Cell Division / Q000276:immunology; D017635:Clonal Anergy / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis*; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006389:Hemagglutinins, Viral / Q000737:chemistry / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
D016207:Cytokines; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006389:Hemagglutinins, Viral; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta; C086595:influenza hemagglutinin (306-318)