A considerable amount of research has focused on elucidating the mechanisms by which cytokines synthesized by cells of the innate immune system participate in the life-threatening multiple-organ failure of endotoxic shock. We show here that alphabeta T cells, which are archetypes of the adaptive cellular immune response, suppress the proinflammatory cascade triggered during the early stages of lipopolysaccharide (LPS)-induced endotoxemia. The absence of alphabeta T cells led to the fulminant death of LPS-challenged mice, coinciding with a massive release of the proinflammatory cytokines tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma and a marked reduction in the synthesis of the immunosuppressive cytokine transforming growth factor (TGF)-beta. Cytotoxic T lymphocyte antigen (CTLA)-positive alphabeta T cells emerging shortly after LPS challenge appear to control TGF-beta synthesis. The neutralization of either TGF-beta or CTLA4 resulted in similar increases in IFN-gamma and TNF-alpha serum concentrations in LPS-challenged mice. These observations suggest that suppressor alphabeta T lymphocytes protect against the proinflammatory cascade unleashed during the innate stages of endotoxemia.