Oral administration of a peptide antigen with the cholera toxin adjuvant induces Th17 rather than Th2 cells

Abstract

Abstract Cholera toxin (CT) is widely used an as adjuvant to elicit mucosal immune responses to co-administered antigens. The observation that antigens given orally with CT induce IL-4-producing T cells and antigen-specific IgE has led to the concept that CT is a Th2 adjuvant. We revisited this issue by using a peptide:MHCII tetramer-based approach to follow the fate of polyclonal CD4+ T cells specific for an MHCII-bound peptide from Toxoplasma gondii CD4Ag28m in mice fed with this peptide and CT. We found that this regimen induced the clonal expansion of CD4Ag28m peptide-specific CD4+ T cells in the secondary lymphoid organs. Surprisingly, the expanded tetramer-binding population consisted of 20 percent RORgt+ Th17 cells but only 3 percent Th2 cells. Th17 cell generation induced by oral peptide plus CT immunization was lost in mice lacking IL-6 or the microbe sensor MyD88. The latter result raised the possibility that the adjuvanticity of CT depended on gut microbes. Treatment of B6 mice with antibiotics to eradicate commensal bacteria, however, only slightly reduced Th17 cell formation in response to oral administration of the peptide plus CT, raising the possibility that viral or fungal microbes are required. Collectively, our data demonstrate that CT induces a Th17 immune response via a pathway that depends on MyD88.