CLEC9A

Official Full Name

C-type lectin domain containing 9A

Organism

Homo sapiens

GeneID

283420

Background

CLEC9A is a group V C-type lectin-like receptor (CTLR) that functions as an activation receptor and is expressed on myeloid lineage cells (Huysamen et al., 2008 [PubMed 18408006]).[supplied by OMIM, Aug 2008]

Synonyms

CD370; DNGR1; DNGR-1; UNQ9341;

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Detailed Information

Dendritic cells (DCs) are professional antigen-presenting cells (APCs) with antigen recognition molecules on the surface. Clec9A is a homodimeric type II transmembrane protein with a single extracellular C-type lectin-like domain. Clec9A is selectively expressed on mouse CD8α⁺ DCs and CD103⁺ DCs subsets, which are functionally similar to human BDCA3⁺ DCs. Clec9A also marks common dendritic cell progenitors (CDPs) and pre-conventional DCs (cDCs) in the bone marrow but it is only maintained on CD8α⁺/CD103⁺ DCs and lost in other cDC subsets. Fate mapping of Clec9A⁺ cells and their progeny through indelible genetic marking indicates that Clec9A expression is highly restricted to cDC/pDC lineages in mice. In humans, Clec9A expression is similarly restricted to CD141⁺ DCs in diverse lymphoid and nonlymphoid organs but is absent from pDCs. Therefore, it seems Clec9A represents an evolutionary conserved, specific marker of Batf3-dependent cDCs subsets that are characterized by superior cross-presentation capacity. Recently, Clec9A has been a very promising target to the DC vaccines for anti-tumor use.

Clec9A and anti-tumor immunity

Clec9A was originally found to be needful for efficient cross-presentation of necrotic cell-associated Ags by CD8α+ DCs, but was shown to be dispensable for Ag uptake and activation of CD8α⁺ DCs. CD8⁺ T cell responses against tumors and cytocidal viruses (e.g. Herpes simplex virus-1, Vaccinia virus,) are impaired in the absence of Clec9A. Antigen targeting DCs by Clec9A could strongly enhance anti-tumor immunity. Other evidence also demonstrated that antigen targeting Clec9A can enhance immune responses of CD4⁺ T cell, CD8⁺ T cell and B cell. Interestingly, even in the absence of adjuvant, antigen targeting Clec9A can also promote powerful humoral immunity and drive long effective development of follicular helper T cells, different from that of antigen targeting DEC205. Further study suggested that the Clec9A can specifically recognize F-actin, a main component of the cellular cytoskeleton exposed by necrotic cells, and initiate cross-priming of DCs to CD8⁺ T cell response against dead cell-associated antigens. These results indicated that Clec9A is a DC-restricted marker sensing damaged cells and antigens, thus targeting Clec9A⁺ DC can promote cellular and humoral immunity. In fact, Clec9A antibody conjugated with antigen could improve the cross-priming of DC cells, and stimulate cytotoxic T lymphocytes (CTLs) response to elicit anti-tumor effects.

CLEC9A Figure 1. Functional specializations of CLEC9A⁺ DC suggest a key role in virus-specific and tumor-specific immunity. (van der Aa E, et al. 2015)

Enhancing vaccine antibody responses by targeting Clec9A

The nature of the immune response on targeting Ag to Clec9A has been studied in mice using Ag models such as ovalbumin (OVA) and nitrophenol (NP). As expected, excellent cross-presentation of Ag on MHC class I was obtained, resulting in an effective cytotoxic CTL response in the presence of DC activation agents. A surprising finding was that efficient Ag presentation on MHC class II was also obtained, leading to a remarkably high Ab response with a single injection of tiny doses of Ag. Equally surprising was the finding that such a high Ab response could be obtained in the absence of adjuvants and any sign of initial DC activation. Thus, researchers tested if targeting weakly immunogenic putative subunit vaccine Ags to Clec9A could enhance Ab responses to a level likely to be protective. The proposed “universal” influenza Ag, M2e and the enterovirus 71 Ag, SP70 were linked to anti-Clec9A Abs and injected into mice. Targeting these Ags to Clec9A greatly increased Ab titres. For optimal responses, a DC-activating adjuvant and a boost injection were required. Besides, targeting small amounts of Ag to Clec9A served as efficient priming for a conventional boost with higher levels of untargeted Ag. Using this Clec9A-targeted priming, conventional boosting strategy, M2e immunization protected mice from infection with lethal doses of influenza H1N1 virus.

References:

Yan Z, et al. A novel peptide targeting Clec9a on dendritic cell for cancer immunotherapy. Oncotarget, 2016, 7(26): 40437.
Park H Y, et al. Enhancing vaccine antibody responses by targeting Clec9A on dendritic cells. NPJ vaccines, 2017, 2(1): 1-11.
Tullett K M, et al. Targeting CLEC9A delivers antigen to human CD141+ DC for CD4+ and CD8+ T cell recognition. JCI insight, 2016, 1(7).
van der Aa E, et al. BDCA3+ CLEC9A+ human dendritic cell function and development. Seminars in cell & developmental biology. Academic Press, 2015, 41: 39-48.
Kato Y. Investigating the interactions between dendritic cells, T cells and B cells mediated by targeting Clec9A. , 2016.

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