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

Area of Science:

• Immunology
• Vaccinology
• Microbial Pathogenesis

Background:

• Infectious diarrheal diseases pose a significant threat to young children globally.
• Parenteral vaccine adjuvants, like bacterial enterotoxins, can induce mucosal antibodies.
• The potential for parenteral immunization to induce mucosal cellular immunity remains largely unexplored.

Purpose of the Study:

• To investigate if parenteral immunization with a bacterial adjuvant can induce vaccine-specific mucosal cellular immunity.
• To compare the immune response elicited by double-mutant heat-labile toxin (dmLT) with a Toll-like receptor-9 agonist (CpG).
• To elucidate the mechanisms by which dmLT promotes T cell homing to the gut.

Main Methods:

• Intradermal immunization of mice with dmLT or CpG.
• Analysis of antigen-specific CD4+ T cell expansion and gut-homing integrin (α4β7) expression.
• Flow cytometry to assess T-helper cell profiles (Th1, Th17).
• Investigation of dendritic cell (DC) subsets, particularly CD103+ DCs, in mediating T cell migration.
• Utilizing CD103+ DC-deficient mice to assess their role in mucosal immune responses.

Main Results:

• Intradermal dmLT immunization drove antigen-specific CD4+ T cell expansion and α4β7 upregulation, promoting gut homing.
• dmLT induced a balanced T-helper 1 and T-helper 17 (Th1/Th17) response, distinct from the predominantly Th1 response induced by CpG.
• dmLT preferentially engaged CD103+ dendritic cells, which were crucial for T cell migration to the intestinal mucosa.
• Mice lacking CD103+ DCs showed impaired T cell migration to the gut following parenteral immunization.

Conclusions:

• Non-toxic double-mutant heat-labile toxin (dmLT) is a potent adjuvant for inducing antigen-specific T cell immunity in the intestinal tract via parenteral administration.
• The mechanism involves the preferential engagement of CD103+ dendritic cells, leading to T cell expansion, gut-homing, and a balanced Th1/Th17 response.
• This strategy offers a promising avenue for developing next-generation vaccines targeting intestinal pathogens by eliciting mucosal immunity without direct mucosal administration.