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

Abstract

Although a number of studies have examined the development of T-helper cell type 2 (Th2) immunity in different settings, the mechanisms underlying the initiation of this arm of adaptive immunity are not well understood. We exploited the fact that immunization with antigen plus either nucleotide-binding oligomerization domain-containing proteins 1 (Nod1) or 2 (Nod2) agonists drives Th2 induction to understand how these pattern-recognition receptors mediate the development of systemic Th2 immune responses. Here, we show in bone-marrow chimeric mice that Nod1 and Nod2 expression within the stromal compartment is necessary for priming of effector CD4 + Th2 responses and specific IgG1 antibodies. In contrast, sensing of these ligands by dendritic cells was not sufficient to induce Th2 immunity, although these cells contribute to the response. Moreover, we determined that CD11c + cells were the critical antigen-presenting cells, whereas basophils and B cells did not affect the capacity of Nod ligands to induce CD4 + Th2 effector function. Finally, we found that full Th2 induction upon Nod1 and Nod2 activation was dependent on both thymic stromal lymphopoietin production by the stromal cells and the up-regulation of the costimulatory molecule, OX40 ligand, on dendritic cells. This study provides in vivo evidence of how systemic Th2 immunity is induced in the context of Nod stimulation. Such understanding will influence the rational design of therapeutics that could reprogram the immune system during an active Th1–mediated disease, such as Crohn's disease.

Regulation of type 2 immunity to helminths by mast cells

“…19 In this study, dendritic cells were found to be the major hematopoietic cell population required. However, it is still possible that MCs may contribute to optimal Th2 orchestration via NOD signaling in other settings.…”

Nod1 and Nod2 Enhance TLR-Mediated Invariant NKT Cell Activation during Bacterial Infection

“…Nod1 and Nod2 stimulation ultimately leads to NF-kB activation and the subsequent production of proinflammatory cytokines. Nod1/2 activation polarizes humoral responses toward Th2 yet enhances TLR-mediated Th1 immunity (38)(39)(40). These two receptors play critical functions at mucosal surfaces.…”

Muramyl dipeptide responsive pathways in Crohn’s disease: from NOD2 and beyond

“…Magalhaes et al [73] showed that MDP activation of the NOD2-mediated pathway in DCs is insufficient to initiate Th2 immunity in absence of stromal-derived mediators, such as thymic stromal lymphopoientin (TSLP). TSLP is thought to promote Th2 immunity by an up-regulation of the expression of OX40 ligand (OX40L), which is a transmembrane protein expressed by APCs to recognize OX40, a receptor expressed by T cells [74,75].…”

“…Moreover, OX40 deficient mice had diminished capabilities in generating NOD2-drived Th2 immunity [73].…”