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 and 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 cellular 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 reduced the expression of CD4(+) T-cell surface activation markers (CD25 and CD69) and subsequent proliferative responses of anti-CD3-stimulated T cells. CT but not LT-IIa or LT-IIb significantly reduced the expression of CD40 ligand (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 both 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 antigen-presenting cells and T cells and help explain the distinct cytokine profiles observed with type I and type II HLT when used as mucosal adjuvants.
Martin
M
M
Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. michmart@uab.edu
Metzger
D J
DJ
Michalek
S M
SM
Connell
T D
TD
Russell
M W
MW
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D001427:Bacterial Toxins / Q000276:immunology* / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000096:biosynthesis*; D002455:Cell Division; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000276:immunology* / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000276:immunology; D004768:Enterotoxins / Q000276:immunology* / Q000494:pharmacology; D029968:Escherichia coli Proteins; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D009000:Monocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000911:Antibodies, Monoclonal; D001427:Bacterial Toxins; D017252:CD3 Complex; D019013:CD40 Antigens; D016207:Cytokines; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D018664:Interleukin-12; D002772:Cholera Toxin; C027538:heat-labile enterotoxin, E coli