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

Abstract

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.

Generation of protective pneumococcal-specific nasal resident memory CD4+ T cells via parenteral immunization

“…6 to the gut after parenteral immunization. 52 Adjuvant selection may also be important for generating T RM in the nasopharynx. In support of this notion, Allen et al recently demonstrated that the choice of adjuvant influenced the generation of CD4 + T RM in the lung following parenteral immunization with an acellular proteinbased pertussis vaccine, although whether these lung CD4 + T RM were truly antigen-specific was not evaluated.…”

Rotavirus vaccine efficacy: current status and areas for improvement

“…microneedles, therefore bypassing the constraints associated with enteropathy and the requirements for a cold chain. 101 Alternative, potentially low-cost strategies for vaccine production and storage such as transgenic plants seem to be gaining traction as exemplified by the oral delivery of rice expressing cholera toxins. 70 In principle, this approach could also be explored for Rotavirus vaccination.…”

“…Only antigen-specific IgG was present in lung mucosal fluid after intradermal immunization while both IgG and IgA were detected after intranasal delivery. 100 Frederick et al 101 compared the effect of CpG and dmLT in combination with MHC class II CD4 + T cell peptide antigen 2W1S after intramuscular and intradermal ear immunization in mice. dmLT was superior to CpG for expanding and maintaining antigen-specific CD4 + T cells in lymph nodes and spleen and at inducing intestinal homing integrin α4β7 in spleen and mesenteric lymph nodes.…”

“…While CpG leads to a Th1 CD4 + T cell bias, dmLT results in both Th1 and Th17 responses. 101 In brief, adjuvants play a major role in stimulating immune responses, especially with inactivated or subunit vaccines. Although several proven single component and combination of adjuvants are available for parenteral immunization, mucosal adjuvants are harder to develop.…”

Development of an enterotoxigenic Escherichia coli vaccine based on the heat-stable toxin

“…In this respect, dmLT has shown promise as an adjuvant that redirects parenterally administered vaccines to an immune response in the gut. 108 It is our hope that ongoing efforts to develop a safe and immunogenic ST toxoid capable of inducing strong mucosal immune responses in the human gut can importantly complement ETEC vaccine candidates currently in the pipeline to produce a broadly protective ETEC vaccine that can substantially reduce the diarrheal disease burden in LMIC children.…”