Regulation of helper T cell responses to staphylococcal superantigens

Staphylococcal superantigens (sAgs) including toxic shock syndrome toxin-1 (TSST-1) and related enterotoxins are exoproteins with unique immunobiologi cal properties, They bind to major histocompatibility complex (MH-IC) class II molecules of antigen-presenting cells outside the peptide groove, and i nduce massive proliferation of T cells bearing specific V beta determinants . This tri-molecular interaction leads to uncontrolled release of various p roinflammatory cytokines especially interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha), the key cytokines causing sAg-mediated s hock, The effector T cells involved in this hyper-immune response are predo minantly of the T helper-1 (Th1) phenotype, There is also some evidence tha t polarization to a Th2 response with the production of classical anti-infl ammatory cytokines (such as interleukins IL-4 and IL-6) also occurs. Moreov er, the emergence of a novel regulatory T cell (Tr1) subset, producing main ly IL-10 but little or no IL-2 and IL-4, has recently been described follow ing repeated sAg stimulation. In this review, the current knowledge regarding the regulation of T helper cell subsets in response to staphylacoccal sAgs is critically evaluated, an d the role of various cytokines which directly influence T cell differentia tion and polarization is summarized, Particular emphasis is directed toward s pro-inflammatory as well as antiinflammatory and regulatory effector func tions during toxic shock. Based on this-review, we propose that a delayed p roduction of IL-10 by Tr1 cells may be the most prominent driving force in the down-regulation of the Th1 hyper-immune response, and the critical dete rminant for the eventual recovery of the host.