Nod2-Dependent Th2 Polarization of Antigen-Specific Immunity

Abstract

While a number of microbial-associated molecular patterns have been known for decades to act as adjuvants, the mechanisms and the signaling pathways underlying their action have remained elusive. Here, we examined the unfolding of the adaptive immune response induced by Nod2 in vivo upon activation by its specific ligand, muramyl dipeptide, a component of peptidoglycan. Our findings demonstrate that this bacterial sensor triggers a potent Ag-specific immune response with a Th2-type polarization profile, characterized by the induction of IL-4 and IL-5 by T cells and IgG1 Ab responses. Nod2 was also found to be critical for the induction of both Th1- and Th2-type responses following costimulation with TLR agonists. Importantly, the synergistic responses to Nod2 and TLR agonists seen in vivo were recapitulated by dendritic cells in vitro, suggesting that these cells likely play a central role in the integration of Nod2- and TLR-dependent signals for driving the adaptive immune response. Taken together, our results identify Nod2 as a critical mediator of microbial-induced potentiation and polarization of Ag-dependent immunity. Moreover, these findings affect our understanding of Crohn’s diseases pathogenesis, where lack of Nod2-dependent Th2 signaling in a subset of these patients might explain heightened Th1-mediated inflammation at the level of the intestinal mucosa.

Cooperative Regulation of NOTCH1 Protein-Phosphatidylinositol 3-Kinase (PI3K) Signaling by NOD1, NOD2, and TLR2 Receptors Renders Enhanced Refractoriness to Transforming Growth Factor-β (TGF-β)- or Cytotoxic T-lymphocyte Antigen 4 (CTLA-4)-mediated Impairment of Human Dendritic Cell Maturation

“…Among TLRs as widely reported, TLR2 exhibits a dominant role in sensing various agonists, including pathogenassociated molecular patterns of microbes at the cell surface, and is generally considered as major effectuator of proinflammatory responses (8 -10). Interestingly, NLRs like NOD1 or NOD2 often play a dual role; they regulate anti-inflammatory responses as well as polarization of T cells toward skewed Th2 phenotype (11). This presents an interesting conundrum to the functionality of DCs in terms of their maturation during rapidly evolving immunological processes, including effects originating from immunosuppressive effectors such as CTLA-4 or TGF-␤ (12)(13)(14).…”

Nucleotide oligomerization domain-containing proteins instruct T cell helper type 2 immunity through stromal activation

“…Although many naturally occurring allergens and allergenic extracts are used to study Th2-driven responses, these preparations often are contaminated with multiple MAMPs (13,14), thereby confounding the interpretation of the specific roles of different MAMPs in the generation of Th2 immunity in these contexts. The agonists that activate Nod1 and Nod2 receptors are chemically defined and have been shown to induce Th2 immunity (15,16), although the mechanisms underlying this response remain ill-defined.…”

Intracellular Pathogen Sensor NOD2 Programs Macrophages to Trigger Notch1 Activation

“…Albeit a integral component of bacterial peptidoglycan, MDP, a well characterized ligand for NOD2, is known for its adjuvant properties; interestingly, unlike many TLR agonists, its engagement with NOD2 receptor preferentially drives Th2 skewed immune responses, which are generally associated with the anti-inflammatory M2 phenotype of macrophages (5)(6)(7). Importantly, natural mutations in the NOD2 gene have been reported to be associated with genetic predisposition to severe inflammatory diseases like Crohn disease, asthma, chronic inflammatory bowel disease etc.…”