Nucleotide Oligomerization Binding Domain-Like Receptor Signaling Enhances Dendritic Cell-Mediated Cross-Priming In Vivo

Abstract

Nucleotide oligomerization binding domain (Nod)-like receptors are critical cytosolic sensors for the recognition of bacterial peptidoglycan. However, their role in the induction of dendritic cell (DC)-mediated cross-priming remains unclear. In this study, we demonstrate that injecting ligands for Nod1 and Nod2 along with Ag into wild-type mice significantly enhanced the cross-priming of Ag-specific CD8+ T cells by CD8α+ DCs, as assessed from the expansion of IFN-γ+ CD8+ T cells, CTL activity against Ag-pulsed targets, and the rejection of transplanted tumors expressing the cognate Ag. The enhancement of CD8α+ DC-mediated cross-priming was likely due to the upregulation of Ag cross-presentation and of costimulatory molecules. Our findings collectively indicate that Nod1/2 signaling is critical for the optimal induction of DC cross-priming in vivo, which may offer an alternative therapeutic pathway in cancer and hosts refractory to TLR signals or paralyzed by viral evasion strategy.

TLR and Nucleotide-Binding Oligomerization Domain-like Receptor Signals Differentially Regulate Exogenous Antigen Presentation

“…Synergistic or antagonistic effects may occur (49). Nod ligands injected into mice concomitant with OVA resulted in enhanced cross-priming, which was in part due to up-regulation of co-stimulatory molecules (50). TLR triggering through signals delivered together with antigenic material during phagocytosis or endocytosis enhances cross-presentation and cross-priming (16, 51, 52).…”

The protein Nod2: An innate receptor more complex than previously assumed

“…In another very recent work, Nod signalling was shown to enhance DCs-mediated cross-priming [81]. DCs have the unique ability to deliver exogenous Ag to the MHC class I-restricted Ag presentation pathway and generate CD8 + T cell immunity to viral infection and cancer, a phenomenon known as cross-priming [82].…”

The ever-expanding function of NOD2: autophagy, viral recognition, and T cell activation

“…Consistent with this observation, the antigen-specific proliferation of autologous CD4 + T cells was reduced after siRNA-mediated silencing of NOD2 or ATG16L1 in DCs. More recently, Nod signaling was shown to enhance Ag cross-presentation, or cross priming, by DCs [51]. Ag cross-presentation denotes the ability of DCs to endocytose, process and present extracellular antigens with MHC class I molecules to CD8 + T cells to generate cytotoxic CD8 + T cell (CTL) immunity to tumors and viral infections that do not infect DCs.…”

“…Ag cross-presentation denotes the ability of DCs to endocytose, process and present extracellular antigens with MHC class I molecules to CD8 + T cells to generate cytotoxic CD8 + T cell (CTL) immunity to tumors and viral infections that do not infect DCs. In this study, DCs stimulated with MDP exhibited increased expression of co-stimulatory and cross-presentation-associated molecules [51]. In addition, injection of Nod agonist into wild type mice significantly enhanced the ability of DCs cells to cross-prime Ag-specific CD8 + T cells as indicated by the increased CTL activity against peptide-pulsed target cells, as well as in vivo anti-tumor CTL activity [51].…”

“…In this study, DCs stimulated with MDP exhibited increased expression of co-stimulatory and cross-presentation-associated molecules [51]. In addition, injection of Nod agonist into wild type mice significantly enhanced the ability of DCs cells to cross-prime Ag-specific CD8 + T cells as indicated by the increased CTL activity against peptide-pulsed target cells, as well as in vivo anti-tumor CTL activity [51]. Taken together, there is accumulating evidence suggesting the NOD2 signaling in antigen-presenting cells, particularly DCs, can positively influence the maturation of the host adaptive immune response.…”