Controlling immune responses by targeting antigens to dendritic cell subsets and B cells

Abstract

Delivering antigens in vivo by coupling them to mAbs specific for unique receptors on antigen-presenting cells (APCs) is a promising approach for modulating immune responses. Antigen delivery to receptors found on myeloid dendritic cell (DC) subsets, plasmacytoid DCs and B cells has shown them all to be viable targets to stimulate either the cellular or humoral arms of the immune system. It is now evident that antigen-targeting approaches can also be used to invoke antigen-specific inhibition of immune responses. The outcome of activation versus inhibition is determined by a combination of factors that include the choice of APC, the receptor that is targeted, whether to include an adjuvant and, if so, which adjuvant to employ. In addition to their use as a means to modulate immune responses, antigen-targeting systems are also a useful method to investigate the function of DC subsets and the early mechanistic events that underlie the initiation of both cellular and humoral immune responses. In this review, we focus on the literature surrounding the control of B-cell responses when antigen is delivered to various APC subsets.

Targeting Antigens through Blood Dendritic Cell Antigen 2 on Plasmacytoid Dendritic Cells Promotes Immunologic Tolerance

“…Our results thus far suggest BDCA2-mediated tolerance induction may operate via a distinct mechanism compared to what occurs after Ag targeting to other receptors (1). Ag delivery to DEC205 on CD8α + DCs, when administered in low doses in the absence of adjuvant, induces CD4 + T cell tolerance mediated by de novo induction of T reg cells (48).…”

“…It was recently shown that binding of mAbs to the transferrin receptor redirects its native intracellular trafficking (i.e., when bound by its natural ligand, transferrin) from recycling endosomes to late endosomal compartments (61). The extent to which mAb binding affects the internalization pathways of receptors such as BDCA2 and Siglec-H is not known and may be one factor that contributes to the differences in outcomes following targeting Ag to different receptors on pDCs (1). …”

“…A simple approach- Ag targeting- has made it possible to deliver an Ag to a particular dendritic cell (DC) 3 subset and thereby program a characteristic immune response: Ag is coupled to a mAb specific for a receptor expressed only or mainly on a DC subpopulation, and then the Ag-mAb complex is injected alone or with an adjuvant (1, 2). Members of the C-type lectin receptor (CLR) family have been chosen as targets because many CLRs are differentially expressed on DC populations and indeed, have been used for defining DC subsets (3-5).…”

Antigen targeting reveals splenic CD169+ macrophages as promoters of germinal center B‐cell responses

“…Because of their potent capacity to capture, process, and present Ag to T cells, Ag-targeting studies have focused on subsets of DCs and improved CTL responses against tumors [3][4][5][6][7][8]. More recently the induction of humoral immunity via Ag targeting to DC subsets has gained renewed interest [9][10][11][12][13][14][15][16].…”

Pros and Cons of Antigen-Presenting Cell Targeted Tumor Vaccines

“…Since the disentanglement of the heterogeneity of different APC subtypes, their specific targeting paved the way towards fundamental research on the exact therapeutic role of each APC subset in antitumor immunotherapy. Moreover, DC subtype specific targeting has already been reported for CLEC9A/BDCA-3 (murine/human cDC1), DCIR-2 (murine cDC2), BDCA-2 (human pDCs), SiglecH and BST2 (murine pDCs), and langerin (LCs) and showed promising differences in the elicited immune responses as a reflection of the specific function of these DC subtypes in situ [11,81,[131][132][133][134][135]. However, DC subset specific functions are not fixed but vary among several factors such as species and inflammatory state.…”