DNGR-1, a Dendritic Cell-Specific Sensor of Tissue Damage That Dually Modulates Immunity and Inflammation

Abstract

DNGR-1 (encoded by CLEC9A) is a C-type lectin receptor (CLR) with an expression profile that is mainly restricted to type 1 conventional dendritic cells (cDC1s) both in mice and humans. This delimited expression pattern makes it appropriate for defining a cDC1 signature and for therapeutic targeting of this population, promoting immunity in mouse models. Functionally, DNGR-1 binds F-actin, which is confined within the intracellular space in healthy cells, but is exposed when plasma membrane integrity is compromised, as happens in necrosis. Upon F-actin binding, DNGR-1 signals through SYK and mediates cross-presentation of dead cell-associated antigens. Cross-presentation to CD8⁺ T cells promoted by DNGR-1 during viral infections is key for cross-priming tissue-resident memory precursors in the lymph node. However, in contrast to other closely related CLRs such as Dectin-1, DNGR-1 does not activate NFκB. Instead, recent findings show that DNGR-1 can activate SHP-1 to limit inflammation triggered by heterologous receptors, which results in reduced production of inflammatory chemokines and neutrophil recruitment into damaged tissues in both sterile and infectious processes. Hence, DNGR-1 reduces immunopathology associated with tissue damage, promoting disease tolerance to safeguard tissue integrity. How DNGR-1 signals are conditioned by the microenvironment and the detailed molecular mechanisms underlying DNGR-1 function have not been elucidated. Here, we review the expression pattern and structural features of DNGR-1, and the biological relevance of the detection of tissue damage through this CLR.

Keywords: C-type lectin receptor; Clec9a; DNGR-1; cross-presentation; dendritic cells; immunity; inflammation.

Figure 1

Duality of DNGR-1 in promoting cross-presentation and limiting inflammation. (A) Upon recognition of F-actin, DNGR-1 signals through the spleen tyrosine kinase (SYK). Signaling of DNGR-1 through SYK diverts phagocytosed cargo toward non-degradative, non-acidic, non-lysosomal compartments. This is a key step for cross-presenting dead cell-associated antigens, which is necessary for the optimal generation of resident memory CD8⁺ T cells in peripheral tissues. (B) Also, DNGR-1 may activate the SH2 domain-containing phosphatase 1 (SHP-1), through a mechanism that might involve SYK, dampening NFκB activation triggered by heterologous receptors; this process limits tissue inflammation by dampening the recruitment of neutrophils to inflammatory foci. Whether both processes occur simultaneously or whether other factors (such as ligand affinity or avidity, ligand binding duration, environmental pH, or ionic strength) determine the signaling modality of DNGR-1 is not known yet.