Revealing the influence of superantigens on the innate immune system

Superantigens (SAgs) are microbial toxins that are known to play a role in food poisoning, toxic shock syndrome and have been identified as a potential mediator of autoimmunity. Staphylococcus aureus, a primary source of bacterial superantigen, is also known to colonize the human respiratory tract and studies have documented a role for SAgs in respiratory disorders. The detrimental effects caused by SAgs occur primarily because of massive clonal expansion of T cells bearing specific TCR Vβ chains followed by subsequent release of pro-inflammatory cytokines. Although much is known about the effects of SAgs on T cells, by comparison few studies have investigated how SAgs influence activation, function and migratory characteristics of innate immune cells. In particular not many studies have examined how SAgs affect dendritic cells, an important innate immune component. In vivo intraperitoneal administration of Staphylococcal enterotoxin A (SEA) revealed a clear dichotomy in the effects of SAgs on conventional (cDCs) versus plasmacytoid DCs (pDCs). While pDCs strictly required IFNγ for upregulation of costimulatory molecules and for recruitment to marginal zones of lymphoid organs, cDCs were not dependent on IFNγ for activation or migration. Intranasal SEA exposure resulted in increased percentage and total number of CD11c+ cells in the lung. One day following intranasal SEA challenge, there was rapid accumulation of CD11c+ cells expressing medium to high levels of MHC II, while the peak accumulation of CD11c + MHC II- population was observed 2 days after SEA challenge. Lung pathology, observed 2 days after SEA exposure, had characteristics of both obstructive and restrictive pulmonary disorders. Massive CD8 +Vβ3+ T cell accumulation was observed in the lung following SEA exposure and was one of the primary sources of IFNγ synthesis. Depletion of CD8 T cells abrogated pathological features observed after SEA exposure. IFNγ deficiency also prevented SEA mediated disease, and this was by enhancing early recruitment of neutrophils as detected in the bronchoalveolar lavage (BAL). Thus this thesis reveals the influence of SAgs on the innate immune system mediated through the action of T cells and IFNγ.