Cross‐presentation of dead‐cell‐associated antigens by DNGR‐1
            +
            dendritic cells contributes to chronic allograft rejection in mice

BackgroundConventional type 1 dendritic cells (cDC1s) are central to antitumor immunity and their presence in the tumor microenvironment associates with improved outcomes in patients with cancer. DNGR-1 (CLEC9A) is a dead cell-sensing receptor highly restricted to cDC1s. DNGR-1 has been involved in both cross-presentation of dead cell-associated antigens and processes of disease tolerance, but its role in antitumor immunity has not been clarified yet.MethodsB16 and MC38 tumor cell lines were inoculated subcutaneously into wild-type (WT) and DNGR-1-deficient mice. To overexpress Flt3L systemically, we performed gene therapy through the hydrodynamic injection of an Flt3L-encoding plasmid. To characterize the immune response, we performed flow cytometry and RNA-Seq of tumor-infiltrating cDC1s.ResultsHere, we found that cross-presentation of tumor antigens in the steady state was DNGR-1-independent. However, on Flt3L systemic overexpression, tumor growth was delayed in DNGR-1-deficient mice compared with WT mice. Of note, this protection was recapitulated by anti-DNGR-1-blocking antibodies in mice following Flt3L gene therapy. This improved antitumor immunity was associated with Batf3-dependent enhanced accumulation of CD8+ T cells and cDC1s within tumors. Mechanistically, the deficiency in DNGR-1 boosted an Flt3L-induced specific inflammatory gene signature in cDC1s, including Ccl5 expression. Indeed, the increased infiltration of cDC1s within tumors and their protective effect rely on CCL5/CCR5 chemoattraction. Moreover, FLT3LG and CCL5 or CCR5 gene expression signatures correlate with an enhanced cDC1 signature and a favorable overall survival in patients with cancer. Notably, cyclophosphamide elevated serum Flt3L levels and, in combination with the absence of DNGR-1, synergized against tumor growth.ConclusionDNGR-1 limits the accumulation of tumor-infiltrating cDC1s promoted by Flt3L. Thus, DNGR-1 blockade may improve antitumor immunity in tumor therapy settings associated to high Flt3L expression.

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Prevention of Acute and Chronic Allograft Rejection by Combinations of Tolerogenic Dendritic Cells

Scandinavian Journal of Immunology ◽

10.1111/j.1365-3083.2010.02485.x ◽

2011 ◽

Vol 73 (2) ◽

pp. 91-101 ◽

Cited By ~ 8

Author(s):

Y. L. Huang ◽

Y. Z. Wang ◽

J. B. Chen ◽

F. Wang ◽

X. P. Kang ◽

...

Keyword(s):

Dendritic Cells ◽

Allograft Rejection ◽

Chronic Allograft Rejection ◽

Tolerogenic Dendritic Cells

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DNGR-1 in dendritic cells limits tissue damage by dampening neutrophil recruitment

Science ◽

10.1126/science.aan8423 ◽

2018 ◽

Vol 362 (6412) ◽

pp. 351-356 ◽

Cited By ~ 38

Author(s):

Carlos del Fresno ◽

Paula Saz-Leal ◽

Michel Enamorado ◽

Stefanie K. Wculek ◽

Sarai Martínez-Cano ◽

...

Keyword(s):

Dendritic Cells ◽

Tissue Damage ◽

Inflammatory Responses ◽

Tissue Injury ◽

Necrotizing Pancreatitis ◽

Neutrophil Recruitment ◽

Dead Cell ◽

Cross Presentation ◽

Conventional Type

Host injury triggers feedback mechanisms that limit tissue damage. Conventional type 1 dendritic cells (cDC1s) express dendritic cell natural killer lectin group receptor-1 (DNGR-1), encoded by the gene Clec9a, which senses tissue damage and favors cross-presentation of dead-cell material to CD8+ T cells. Here we find that DNGR-1 additionally reduces host-damaging inflammatory responses induced by sterile and infectious tissue injury in mice. DNGR-1 deficiency leads to exacerbated caerulein-induced necrotizing pancreatitis and increased pathology during systemic Candida albicans infection without affecting fungal burden. This effect is B and T cell–independent and attributable to increased neutrophilia in DNGR-1–deficient settings. Mechanistically, DNGR-1 engagement activates SHP-1 and inhibits MIP-2 (encoded by Cxcl2) production by cDC1s during Candida infection. This consequently restrains neutrophil recruitment and promotes disease tolerance. Thus, DNGR-1–mediated sensing of injury by cDC1s serves as a rheostat for the control of tissue damage, innate immunity, and immunopathology.

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