Distinct cytokine regulation by cholera toxin and type II heat-labile toxins involves differential regulation of CD40 ligand on CD4(+) T cells

Cholera toxin (CT) and the type II heat-labile enterotoxins (HLT) LT-IIa an d LT-IIb act as potent systemic and mucosal adjuvants and induce distinct T -helper (Th)-cell cytokine profiles. In the present study, CT and the type II HLT were found to differentially affect cytokine production by anti-CD3- stimulated human peripheral blood mononuclear cells (PBMC), and the cellula r mechanisms responsible were investigated. CT suppressed interleukin-2 (IL -2), tumor necrosis factor alpha (TNF-alpha), and IL-12 production by PBMC cultures more than either LT-IIa or LT-IIb, CT but not LT-IIa or LT-IIb red uced the expression of CD4(+) T-cell surface activation markers (CD25 and C D69) and subsequent proliferative responses of anti-CD3-stimulated T cells. CT but not LT-IIa or LT-IIb significantly reduced the expression of CD40 l igand (CD40L) on CD4(+) T cells, In a coculture system, CT-treated CD4(+) T cells induced significantly less TNF-alpha and IL-12 p70 production by bot h autologous monocytes and monocyte-derived dendritic cells than either LT- IIa- or LT-IIb-treated CD4(+) T cells. These findings demonstrate that CT, LT-IIa, and LT-IIb differentially affect CD40-CD40L interactions between an tigen-presenting cells and T cells and help explain the distinct cytokine p rofiles observed with type I and type II HLT when used as mucosal adjuvants ,