The C-Type Lectin Clec12A Present on Mouse and Human Dendritic Cells Can Serve as a Target for Antigen Delivery and Enhancement of Antibody Responses

The dendritic cell (DC) immunoreceptors (DCIR) and DC-immunoactivating receptors (DCAR) represent a subfamily of cell surface C-type lectin receptors (CLR), whose multifunctional capacities range from classical Ag uptake and immunoregulatory mechanisms to the involvement in DC ontogeny. On the basis of the generation of specific mAbs, we functionally characterized mouse DCAR1 (mDCAR1) as a member of the DCIR/DCAR family. Expression of mDCAR1 was strongly tissue dependent. mDCAR1 expression on DCs was restricted to the CD8+ DC subset in spleen and thymus and on subpopulations of CD11b+ myeloid cells in bone marrow and spleen, whereas the molecule was not detectable on both cell types in lymph nodes and peripheral blood. With respect to the function of CLRs as pattern recognition receptors, Ag delivered via mDCAR1 was internalized, was trafficked to early and late endosomes/lysosomes and, as a consequence, induced cellular and humoral responses in vivo even in the absence of CD40 stimulation. Intriguingly, upon triggering mDCAR1, CD8+ DCs increased the secretion of bioactive IL-12, whereas IL-10 release is markedly reduced, thereby indicating that Ag recognized by mDCAR1 induces enhanced proinflammatory responses. These data indicate that mDCAR1 is a functional receptor on cells of the immune system and provides further insights into the regulation of immune responses by CLRs.

Section: Discussioncontrasting

confidence: 50%

Enhanced Dendritic Cell-Induced Immune Responses Mediated by the Novel C-Type Lectin Receptor mDCAR1

Kaden

Kurig

Vasters

et al. 2009

“…These mAb-OVA complexes all recognized their target molecules on DCs (Supplemental Fig. 1A) (16,19). Others have shown that the anti-DEC-205 mAb does not directly activate DCs (14).…”

Section: Delivering Ags To Cd8mentioning

confidence: 99%

“…We have already demonstrated that targeting Ags in the form of rat Ig to Clec9A (16), but not Clec12A or DEC-205 (19,27,28), can induce strong Ab responses in the absence of adjuvants. The mAb-OVA constructs behaved as did the original rat mAb: Targeting Clec9A induced potent anti-rat Ig responses ( Fig.…”

Section: Ab Responses Induced By Targeting Ags To Cd8 + DC Surface Momentioning

confidence: 99%

“…In this paper, we compare Ag delivery with three different receptors predominantly expressed on CD8 + DCs: (1) DEC-205 (CD205), a well-established and effective target molecule (13)(14)(15); (2) Clec9A (also known as DNGR-1), a C-type lectin-like molecule with high specificity for CD8 + DCs and their human equivalent (16)(17)(18); and (3) Clec12A, a C-type lectin-like molecule with an intracellular immunoreceptor tyrosine-based inhibition motif and a broad expression pattern (19,20). We found different receptor and adjuvant requirements for generating cellmediated or humoral immunity.…”

mentioning

confidence: 99%

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Targeting Antigen to Mouse Dendritic Cells via Clec9A Induces Potent CD4 T Cell Responses Biased toward a Follicular Helper Phenotype

Lahoud

Ahmet

Kitsoulis

et al. 2011

Self Cite

201

335

Three surface molecules of mouse CD8+ dendritic cells (DCs), also found on the equivalent human DC subpopulation, were compared as targets for Ab-mediated delivery of Ags, a developing strategy for vaccination. For the production of cytotoxic T cells, DEC-205 and Clec9A, but not Clec12A, were effective targets, although only in the presence of adjuvants. For Ab production, however, Clec9A excelled as a target, even in the absence of adjuvant. Potent humoral immunity was a result of the highly specific expression of Clec9A on DCs, which allowed longer residence of targeting Abs in the bloodstream, prolonged DC Ag presentation, and extended CD4 T cell proliferation, all of which drove highly efficient development of follicular helper T cells. Because Clec9A shows a similar expression pattern on human DCs, it has particular promise as a target for vaccines of human application.

“…CD8a 2 CD11b + CDCs have also been targeted successfully leading to preferential expansion of CD4 + T cells and induction of humoral immune responses (6,(11)(12)(13). In the human system, Abs directed against DEC205, DC-SIGN, DCIR, and the mannose receptor were shown to be capable of targeting Ag to human DCs and to trigger CD4 + and CD8 + T cell responses in vitro (3,11,12).…”

mentioning

confidence: 99%

Antigen Delivery to Plasmacytoid Dendritic Cells via BST2 Induces Protective T Cell-Mediated Immunity

Loschko

Schlitzer

Dudziak

et al. 2011

Plasmacytoid dendritic cells (PDCs) are capable of presenting Ags to T cells in a tolerogenic or immunogenic manner depending on the formulation of the Ag and the mode of stimulation. It has not been investigated whether effective adaptive immune responses useful for vaccination can be induced by Ab-mediated Ag targeting to PDCs in vivo. In this study, we show that Ag delivered to murine PDCs via bone marrow stromal cell Ag 2 (BST2)/CD317 in combination with TLR agonists as adjuvants is specifically presented by PDCs in vivo and elicits strong cellular and humoral immune responses. These include IFN-γ production by CD4+ T cells and high Ab titers with a broad range of IgG isotypes. In addition, BST2-mediated Ag delivery in the presence of polyinosinic-polycytidylic acid as adjuvant induces cytotoxic T lymphocytes that are functional in vivo. A single immunization with Ag-fused anti-BST2 Ab together with polyinosinic-polycytidylic acid as adjuvant is sufficient to trigger protective immunity against subsequent viral infection and tumor growth. We conclude that despite the potential tolerogenic properties of PDCs, Ag targeting to PDCs in combination with TLR agonists as adjuvants is an effective vaccination strategy.