Differential Binding of Escherichia coli Enterotoxins LT-IIa and LT-IIb and of Cholera Toxin Elicits Differences in Apoptosis Proliferation and Activation of Lymphoid Cells

摘要

Cholera toxin (CT), LT-IIa, and LT-IIb are potent adjuvants which induce distinct T-helper (Th)-cell cytokine profiles and immunoglobulin G (IgG) subclass and IgA antibody responses. To determine if the distinct immune regulatory effects observed for LT-IIa, LT-IIb, and CT are elicited by binding of the enterotoxins to their cognate ganglioside receptors, the lineages of lymphoid cells that interact with the three enterotoxins and their effects on various lymphocyte responses in vitro were evaluated. Binding patterns of LT-IIa, LT-IIb, and CT to several lymphoid cell populations were distinctive for each enterotoxin. LT-IIa and CT, but not LT-IIb, induced apoptosis in CD8⁺ T cells. LT-IIa(T34I), a mutant with no detectable binding to gangliosides, did not induce apoptosis. Blockade of GM1 on the surface of CD8⁺ T cells by LT-IIa(T14I), a mutant that binds only to GM1 but does not induce apoptosis, did not inhibit induction of apoptosis by LT-IIa. Mitogen-induced proliferation of CD8⁺ T cells was abrogated by treatment with CT, while resting CD8⁺ T cells which were sensitive to LT-IIa-induced apoptosis became more resistant to apoptosis after mitogen activation. Exposure to CT, but not to LT-IIa or LT-IIb, inhibited mitogen-driven CD4⁺ T-cell proliferation and expression of CD25 and CD69. In mitogen-stimulated B cells, CT, but not LT-IIa or LT-IIb, enhanced expression levels of CD86, while only CT induced B-cell differentiation into plasma cells. Thus, LT-IIa, LT-IIb, and CT exhibit distinguishable immunomodulatory properties which are likely dependent upon their capacities to recognize different ganglioside receptors on lymphocytes.