Chimeras of labile toxin one and cholera toxin retain mucosal adjuvanticity and direct Th cell subsets via their B subunit.
Native cholera toxin (nCT) and the heat-labile toxin 1 (nLT) of enterotoxigenic Escherichia coli are AB5-type enterotoxins. Both nCT and nLT are effective adjuvants that promote mucosal and systemic immunity to protein Ags given by either oral or nasal routes. Previous studies have shown that nCT as mucosal adjuvant requires IL-4 and induces CD4-positive (CD4+) Th2-type responses, while nLT up-regulates Th1 cell production of IFN-gamma and IL-4-independent Th2-type responses. To address the relative importance of the A or B subunits in CD4+ Th cell subset responses, chimeras of CT-A/LT-B and LT-A/CT-B were constructed. Mice nasally immunized with CT-A/LT-B or LT-A/CT-B and the weak immunogen OVA developed OVA-specific, plasma IgG Abs titers similar to those induced by either nCT or nLT. Both CT-A/LT-B and LT-A/CT-B promoted secretory IgA anti-OVA Ab, which established their retention of mucosal adjuvant activity. The CT-A/LT-B chimera, like nLT, induced OVA-specific mucosal and peripheral CD4+ T cells secreting IFN-gamma and IL-4-independent Th2-type responses, with plasma IgG2a anti-OVA Abs. Further, LT-A/CT-B, like nCT, promoted plasma IgG1 more than IgG2a and IgE Abs with OVA-specific CD4+ Th2 cells secreting high levels of IL-4, but not IFN-gamma. The LT-A/CT-B chimera and nCT, but not the CT-A/LT-B chimera or nLT, suppressed IL-12R expression and IFN-gamma production by activated T cells. Our results show that the B subunits of enterotoxin adjuvants regulate IL-12R expression and subsequent Th cell subset responses.
Boyaka
Prosper N
PN
Department of Microbiology and Oral Biology, Immunobiology Vaccine Center, University of Alabama, Birmingham, AL 35294, USA.
Ohmura
Mari
M
Fujihashi
Kohtaro
K
Koga
Toshiya
T
Yamamoto
Masafumi
M
Kweon
Mi-Na
MN
Takeda
Yoshifumi
Y
Jackson
Raymond J
RJ
Kiyono
Hiroshi
H
Yuki
Yoshikazu
Y
McGhee
Jerry R
JR
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000235:genetics / Q000502:physiology; D000281:Administration, Intranasal; D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis / Q000097:blood; D001427:Bacterial Toxins / Q000008:administration & dosage* / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000008:administration & dosage* / Q000235:genetics / Q000494:pharmacology; D004768:Enterotoxins / Q000008:administration & dosage* / Q000235:genetics / Q000502:physiology; D029968:Escherichia coli Proteins / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology; D007071:Immunoglobulin A, Secretory / Q000096:biosynthesis / Q000097:blood; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009297:Nasal Mucosa / Q000276:immunology*; D021122:Protein Subunits / Q000008:administration & dosage* / Q000235:genetics / Q000502:physiology; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D053707:Receptors, Interleukin-12; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000235:genetics / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D001427:Bacterial Toxins; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D007071:Immunoglobulin A, Secretory; D007074:Immunoglobulin G; D021122:Protein Subunits; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D011993:Recombinant Fusion Proteins; D002772:Cholera Toxin; C027538:heat-labile enterotoxin, E coli