Induction of responsiveness in superantigen-induced anergic T cells. Role of ligand density and costimulatory signals.
The bacterial superantigen staphylococcal enterotoxin B (SEB) induces in vivo a state of anergy defined by the inability of V beta 8+ CD4+ T cells to produce IL-2 upon restimulation in vitro. However, restimulation in vivo triggers a burst of acutely released lymphokines including IL-2 and TNF, paralleled by up-regulation of lymphokine-specific mRNA. Since anergy as defined in vitro appears not to operate in vivo, we analyzed parameters able to induce responsiveness in anergic T cells. We show here that in vitro stimulation of anergic T cells with competent Ag-presenting cells induces responsiveness, provided the APC (activated B cells or dendritic cells) present high concentrations of SEB. Crosslinking of CD28 molecules on anergic T cells could substitute the requirement for competent APC. Quantitation of TCR threshold by determining the SEB concentrations able to trigger half-maximal T cell responses revealed that anergic and normal T cells exhibited the same TCR threshold for the expression of functional IL-2 receptors (IL-2R), yet the TCR threshold for induction of IL-2 production was 10- to 100-fold elevated in anergic T cells. TCR threshold for normal and anergic T cells was further dependent on the type of APC, i.e., costimulus-competent APC required 100-fold less SEB. The results indicate that extrinsic factors such as ligand concentration and costimulus competence of APC can overcome the heightened TCR threshold of anergic T cells, thus reverting anergy into responsiveness.
Heeg
K
K
Institute of Medical Microbiology and Hygiene, Technical University of Munich, Germany.
Wagner
H
H
D000818:Animals; D001483:Base Sequence; D018106:CD28 Antigens / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology*; D003429:Cross Reactions / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D004768:Enterotoxins / Q000276:immunology* / Q000627:therapeutic use; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D013210:Staphylococcus / Q000276:immunology*; D018089:Superantigens / Q000276:immunology* / Q000627:therapeutic use
D018106:CD28 Antigens; D004768:Enterotoxins; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D018089:Superantigens; C031818:enterotoxin B, staphylococcal