PROTECTION AGAINST LETHAL TOXIC SHOCK BY TARGETED DISRUPTION OF THE CD28 GENE

Toxic shock syndrome (TSS) is a multi system disorder resulting h-om s uperantigen-mediated cytokine production. Nearly 90% of the clinical c ases of TSS arise due to an exotoxin, toxic shock syndrome toxin-1 (TS ST-1), elaborated by toxigenic strains of Staphylococcus aureus. It is clearly established that besides antigen-specific signals a variety o f costimulatory signals are required for full T cell activation. Howev er, the nature and potential redundancy of costimulatory signals are i ncompletely understood, particularly with regards to superantigen-medi ated T cell activation in vivo. Here we report that CD28-deficient mic e (CD28-/-) are completely resistant to TSST-1-induced lethal TSS whil e CD28 (+/-) littermate mice were partially resistant to TSST-1. The m echanism for the resistance of the CD28 (-/-) mice was a complete abro gation of TNF-ol accumulation in the serum and a nearly complete (90%) impairment of IFN-gamma secretion in response to TSST-1 injection. In contrast, the serum level of IL-2 was only moderately influenced by t he variation of CD28 expression. CD28 (-/-) mice retained sensitivity to TNF-alpha as demonstrated by equivalent lethality after cytokine in jection. These findings establish an essential requirement for CD28 co stimulatory signals in TSST-1-induced TSS. The hierarchy of TSST-1 res istance among CD28 wild-type (CD28+/+), CD28 heterozygous (CD28+/-), a nd CD28-/- mice suggests a gene-dose effect, implying that the levels of T cell surface CD28 expression critically regulate superantigen-med iated costimulation. Finally, as these results demonstrate the primary and non-redundant role of CD28 receptors in the initiation of the in vivo cytokine cascade, they suggest therapeutic approaches for superan tigen-mediated immunopathology.