PERTUSSIS TOXIN POTENTIATES T(H)1 AND T(H)2 RESPONSES TO CO-INJECTED ANTIGEN - ADJUVANT ACTION IS ASSOCIATED WITH ENHANCED REGULATORY CYTOKINE PRODUCTION AND EXPRESSION OF THE COSTIMULATORY MOLECULES B7-1, B7-2 AND CD28

Pertussis toxin (PT) is a major virulence factor of Bordetella pertuss is which exerts a range of effects on the immune system, including the enhancement of IgE, IgA and IgG production, delayed-type hypersensiti vity reactions, and the induction of experimental autoimmune diseases. However, the mechanism by which PT mediates adjuvanticity remains to be defined. In this investigation we have shown that PT can potentiate antigen-specific T cell proliferation and the secretion of IFN-gamma, IL-2, IL-4 and IL-5 when injected with foreign antigens, A chemically detoxified PT and a genetic mutant with substitutions/deletions in th e S-1 and a oligomer components that abrogate enzymatic and binding ac tivity displayed no adjuvant properties. In contrast,a non-toxic S-1 m utant devoid of enzymatic activity but still capable of receptor bindi ng retained its adjuvanticity, augmenting the activation of both T(h)1 and T(h)2 subpopulations of T cells. In an attempt to address the mec hanism of T cell activation, we found that PT stimulated the productio n of IFN-gamma and IL-2 by naive T cells and IL-1 by macrophages, Ther efore potentiation of distinct T cell subpopulations may have resulted in part from the positive influence of IFN-gamma on the development o f T(h)1 cells and the costimulatory role of IL-1 for T(h)2 cells, Furt hermore, PT augmented expression of the co-stimulatory molecules B7-1 and B7-2 on macrophages and a cells, and CD28 on T cells, suggesting t hat the adjuvant effect may also be associated with facilitation of th e second signal required for maximal T cell activation. This study dem onstrates that the immunopotentiating properties of PT are largely ind ependent of ADP-ribosyltransferase activity, but are dependent on rece ptor binding activity and appear to involve enhanced activation of T c ells.