INDUCTION OF UNRESPONSIVENESS TO THE SUPERANTIGEN STAPHYLOCOCCAL ENTEROTOXIN-B - CYCLOSPORINE-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 hours 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. In addition they suggest that unresponsiveness (tolerance) can be induced in the presence of CsA.