Enhancement of CD8+ T Cells by the Type II Heat-Labile Enterotoxins LT-IIb and LT-IIc
Hu, John C.
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Vaccination has played a critical role in the prevention of infectious diseases. Not all antigenic targets, however, elicit sufficient or appropriate immune responses that confer immunity. Additionally, protein subunit antigens commonly included in vaccine compositions routinely elicit production of antibodies with minimal induction of antigen-specific CD8+ T cell responses. For control and/or protection, pathogens and diseases such as the human immunodeficiency virus (HIV), hepatitis C virus (HSV), malaria, and tuberculosis require generation of CD8+ T cell immunity. To enhance and shape the immune response for improved efficacy, adjuvants can be employed in vaccine formulations. The type II heat-labile enterotoxins (HLT) are exceptionally potent adjuvants that enhance humoral immune responses against co-administrated antigens. The capacity of these type II HLT to enhance CD8+ T cell responses has not been fully characterized. Using a murine intradermal immunization model, studies presented demonstrate that LT-IIb and LT-IIc, two type II HLT adjuvants, enhance CD8+ T cell responses when co-administered intradermally with a soluble protein antigen. Intriguingly, while LT-IIc induced a more robust early response (~1 week), the antigen-specific CD8+ T cell in LT-IIb adjuvanted mice continued to expand for two weeks. Additionally, experiments revealed that LT-IIb induced a higher percentage of KLRG1+CD127+ effector-memory CD8+ T cells at a time point one month post-vaccination. Furthermore, LT-IIb conferred better clearance and protection against Listeria monocytogenes, an intracellular pathogen, in a murine immunization-challenge model. To explicate this difference in adjuvanticity between LT-IIb and LT-IIc, chimeric HLT adjuvants were engineered in which the A and B subunits of LT-IIb and LT-IIc were interchanged. Using these chimeras, it was determined that the characteristic CD8+ T cell responses induced by LT-IIb and LT-IIc were conferred by their receptor-binding B subunits. Finally, it was demonstrated that both LT-IIb and LT-IIc enhanced activation of dendritic cells (DC) in the draining lymph nodes and that a specific subset of DC that express the BATF3 transcriptional factor, were essential for the CD8+ T cell adjuvant properties of those HLT. Thus, these experiments presented herein confirm that LT-IIb and LT-IIc are potent humoral adjuvants that robustly enhance CD8+ T cell responses, which is a highly desirable trait for developing vaccines for which an augmented Ag-specific CD8+ T cell immune response is also desired.