Cutaneous vaccination with TLR2 agonists results in the suppression of Th1 responses

Abstract

Abstract Novel effective vaccines are key to solving many global health problems. Past efforts to rationally design vaccines that elicit strong cell-mediated responses have largely failed. Vaccine adjuvants, particularly toll-like receptor (TLR) agonists, are a promising tool to shape immune responses by polarizing CD4 T cells to distinct fates. Use of these adjuvants to design novel vaccines requires the full characterization of their effects on CD4 T cell differentiation, particularly in regard to the route of vaccination. In a large scale in vitro screen of vaccine adjuvants, we demonstrated that Pam3CSK4, a synthetic mimic of bacterial lipoproteins with TLR1/2 agonist activity, strongly polarized CD4 T cells to the Th1 fate (IFN-γ+, T-bet+) supporting cell-mediated responses. We adapted a vaccination system to study CD4 T cell polarization in vivo using ovalbumin-specific transgenic CD4 T cells. This in vivo system showed a route-specific effect, with strong Th1 responses from intravenous immunization with ovalbumin plus Pam3CSK4, but a lack of Th1 responses with immunization through more clinically relevant cutaneous routes. Interestingly, Pam3CSK4 in combination with a known Th1 polarizing adjuvant, CpG ODN, showed little to no Th1 response suggesting a dominant suppressive mechanism. Furthermore, suppression of Th1 differentiation occurred in response to both TLR1/2 and TLR6/2 agonists. Using a variety of cell-ablative mouse models we were able to reverse suppression of Th1 responses and identify specific candidates of innate immune cells mediating suppression during vaccination with TLR2 agonists. Current work focuses on mechanisms of suppression by TLR2 agonists in the skin and relevance to improving vaccine design.