Adjuvant selection regulates gut migration and phenotypic diversity of antigen-specific CD4(+) T cells following parenteral immunization.

Infectious diarrheal diseases are the second leading cause of death in children under five, making vaccines against these diseases a high priority. It is known that certain vaccine adjuvants, chiefly bacterial ADP-ribosylating enterotoxins, can induce mucosal antibodies when delivered parenterally. Based on this, we reasoned vaccine-specific mucosal cellular immunity could be induced via parenteral immunization with these adjuvants. Here, we show that, in contrast to the TLR9 agonist CpG, intradermal immunization with non-toxic double-mutant heat-labile toxin from enterotoxigenic E. coli drives endogenous, antigen-specific CD4(+) T cells to expand and upregulate the gut-homing integrin α4β7. This was followed by T cell migration into gut-draining lymph nodes and both small and large intestines. We also find dmLT produces a balanced Th1 and Th17 response whereas T cells from CpG immunized mice are predominantly Th1. Immunization with dmLT preferentially engages CD103(+) dendritic cells compared to CpG, and mice deficient in CD103(+) dendritic cells were unable to fully license antigen-specific T cell migration to the mucosae following parenteral immunization. This work has the potential to redirect the design of existing and next generation vaccines to elicit pathogen-specific immunity in the intestinal tract with non-mucosal immunization.