The TLR2 Binding Neisserial Porin PorB Enhances Antigen Presenting Cell Trafficking and Cross-presentation

Abstract

TOLL-like receptor (TLR) ligands activate both innate and adaptive immune cells, while modulating the cellular immune response. The outer membrane protein (OMP) from Neisseria meninigitidis, PorB, is a naturally occurring TLR2 ligand and functions as an adjuvant. Here, we demonstrate that PorB increases the level of OVA in the endo-/lysosomal cellular compartment of BMDCs, increases antigen presenting cell (APC) trafficking to draining lymph nodes, and enhances antigen cross-presentation. PorB is capable of mounting an antigen specific T cell response by efficiently stimulating antigen cross-presentation in vivo and in vitro assessed by BMDC OT-I cocultivation assays. The enhanced antigen cross-presentation and the increased APC recruitment to secondary lymphoid tissues expand the scope of known adjuvant effects of PorB on the immune system. Our findings lead to a better understanding of how TLR-ligand based adjuvants can alter and modulate immune responses.

Toll-Like Receptor Ligand Based Adjuvant, PorB, Increases Antigen Deposition on Germinal Center Follicular Dendritic Cells While Enhancing the Follicular Dendritic Cells Network

“…PorB is a TLR2/1 ligand, and is able to significantly increase co-stimulatory ligand expression and cytokine production in antigen presenting cells (APC) (44). In addition, PorB can increase antigen loaded APC trafficking to the lymph node (45), induce germinal center formation (46), and enhance antigen specific antibody production, CD4 + T cell activation (47), and cross presentation allowing for CD8 + T cell activation (45). We have mainly used subcutaneous immunizations for these studies; however, the effect of adjuvants of the microenvironment of the draining lymph nodes from these injections has not be extensively investigated.…”

Neisserial PorB immune enhancing activity and use as a vaccine adjuvant

“…By continuing these types of studies, and communicating findings in a consistent manner, (1) PorB recognition by TLR1/2 on antigen presenting cells (APCs) at the site of injection leads to TLR2 and MyD88-dependent signaling for increased costimulatory molecule expression and secretion of Th1 and Th2 cytokines as shown by Platt et al 22 and Mosaheb et al 23 (2) Enhanced APC activation promotes trafficking of APCantigen to secondary lymphoid organs (SLOs) and (3) antigen uptake and processing for classical and cross-presentation inducing activation of antigen-specific CD4 + (as shown in green) and CD8 + T cells (as shown in blue). 24 (4) PorB enhances germinal center (GC) formation and production of both Th1 and Th2 IgGs. 23,24 Follicular dendritic cell (FDC); CD4 + T follicular helper cells (Tfh); Memory B cell (MBC); Antibody secreting cell (ASC) the vaccine field will continue to advance, allowing for improved vaccines.…”

“…24 (4) PorB enhances germinal center (GC) formation and production of both Th1 and Th2 IgGs. 23,24 Follicular dendritic cell (FDC); CD4 + T follicular helper cells (Tfh); Memory B cell (MBC); Antibody secreting cell (ASC) the vaccine field will continue to advance, allowing for improved vaccines. The prospect of reducing disease burden is exciting and of utmost importance especially when considering diseases for which there is no efficient vaccine such as HIV, TB, and malaria.…”

“…A recent publication from our lab focused on the ability of PorB to increase antigen trafficking to the lymph node and cross-presentation of antigen by dendritic cells. 24 This observation led to our exploration of PorB's effect on CD4 + and CD8 + T cell populations. Most recently, our group has shown that PorB adjuvanted vaccination of mice using the model antigen ovalbumin (OVA) results in an increase of IL-4 and IFNγ positive CD4 + and CD8 + T cells.…”

“…As a vaccine adjuvant, PorB increases the expression of co-stimulatory factors and cytokines by APCs, increases antibody production, improves antigen trafficking to the lymph node, and promotes a broad T cell response including effective cross-presentation allowing for both CD4 and CD8 T cell responses. [23][24][25] A visual representation of PorB's effects in relation to vaccine adjuvanticity is displayed in Figure 2.…”