Induction of unresponsiveness to the superantigen staphylococcal enterotoxin B: cyclosporin A resistant split unresponsiveness unfolds in vivo without preceding clonal expansion.
The continuous presence of antigen and powerful immune responses (exhaustive cell proliferation) of ligand reactive T cells are currently thought to condition clonal deletion and/or induction of unresponsiveness to endogenous or exogenous superantigens (SAg). Here we report that in vivo induction of unresponsiveness to the SAg staphylococcal enterotoxin B (SEB) can be an immediate process. Within ours a large portion of ligand reactive V beta 8+ T cells becomes clonally deleted by apoptosis. In parallel, the remaining V beta 8+ T cells are unresponsive to SEB, yet at the same time express functional IL-2 receptors (IL-2R) and thus are highly responsive to the growth promoting effects of IL-2. In a subsequent step refractory IL-2R+V beta 8+ T cells undergo a wave of cell proliferation for 48 h, presumably driven by IL-2. Thereafter a large proportion of V beta 8+ T cells succumb to apoptosis, the remaining cells display the hallmarks of split unresponsiveness, i.e. they display a selective failure to produce IL-2 upon SEB stimulation in vitro combined with a preserved capability to express functional IL-2R. Early deletion and induction of unresponsiveness to SEB are cyclosporin A (CsA) resistant, while clonal expansion with subsequent cell deletion is blocked by CsA, yet the development of split unresponsiveness is not impaired by CsA. The results suggest that IL-2 driven growth of refractory T cells may mimic powerful immune responses of ligand reactive V beta 8+ T cells. Since unresponsiveness to SEB precedes in vivo expansion, the results as such question the concept of 'exhaustive cell proliferation' as a prerequisite for induction of unresponsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)
Institute of Medical Microbiology and Hygiene, Technical University of Munich, Germany.
K
K
Heeg
S
S
Bendigs
T
T
Miethke
H
H
Wagner
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D004768:Enterotoxins / Q000276:immunology*; D007108:Immune Tolerance; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D013211:Staphylococcus aureus / Q000276:immunology*; D018089:Superantigens / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D004768:Enterotoxins; D007376:Interleukin-2; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018089:Superantigens; C031818:enterotoxin B, staphylococcal; D016572:Cyclosporine