Oligodeoxynucleotides Without CpG Motifs Work as Adjuvant for the Induction of Th2 Differentiation in a Sequence-Independent Manner

The macrophage class A scavenger receptors, macrophage receptor with a collagenous structure (MARCO) and type I/II class A scavenger receptor (SR-AI/II), share structural features and roles in host defense, but little is known about their regulation and signaling properties. Ligation of MARCO on mouse thioglycollate-elicited peritoneal macrophages (PEMs) with immobilized mAb costimulated IL-12 production, in contrast to previously reported inhibition by SR-AI/II. PEMs from MARCO-deficient mice exhibited 2.7 times lower IL-12 production in responses to stimulation with LPS and IFN-γ and lack of significant IL-12 production on stimulation with LPS alone. Conversely, SR-AI/II-deficient PEMs produced 2.4 and 1.8 times more IL-12 than wild-type PEMs in response to LPS or LPS and IFN-γ, respectively. Corresponding differences in regulation of SR-A and MARCO expression were also observed. Th1 adjuvants (LPS, a CpG motif-containing oligodeoxynucleotide (CpG-ODN), IL-12, and GM-CSF) increased, whereas Th2-polarizing factors (IL-4, M-CSF, and non-CpG ODN) decreased expression of MARCO on J774 macrophage-like cells. Expression of SR-A was regulated in the opposite manner to MARCO or not affected. Whereas MARCO was involved in opsonin-independent phagocytosis in CpG-ODN-pretreated but not in IL-4-pretreated J774 cells, anti-SR-A Abs inhibited particle uptake in untreated and IL-4-pretreated but not in CpG-ODN-pretreated cells. SR-A and MARCO are regulated differently and mediate distinct negative and positive effects on IL-12 production in macrophages. These differences may contribute to sustained Th1 or Th2 polarization of ongoing immune responses.

Section: Th1-polarizing and Th2-polarizing Factors Have Opposite Effementioning

confidence: 90%

Disparate Regulation and Function of the Class A Scavenger Receptors SR-AI/II and MARCO

Józefowski

Arredouani

Sulahian

et al. 2005

“…2). Although T cells do not bind ODN as effectively as APCs (33,34), preliminary studies in our laboratory established that FITC-labeled suppressive ODN do bind CD3 ϩ T cells (data not shown). In this context, Halpern and Pisetsky (35) recently demonstrated that poly(G) ODN inhibit IFN-␥ production by polyclonally activated T cells.…”

Section: Discussionmentioning

confidence: 99%

Suppressive Oligodeoxynucleotides Inhibit Th1 Differentiation by Blocking IFN-γ- and IL-12-Mediated Signaling

Shirota

Gürsel

Klinman

2004

Self Cite

Repetitive TTAGGG motifs present at high frequency in mammalian telomeres can suppress Th1-mediated immune responses. Synthetic oligonucleotides (ODN) containing TTAGGG motifs mimic this activity and have proven effective in the prevention/treatment of certain Th1-dependent autoimmune diseases. This work explores the mechanism by which suppressive ODN block the induction of Th1 immunity. Findings indicate that these ODN inhibit IFN-γ-induced STAT1 phosphorylation and IL-12-induced STAT3 and STAT4 phosphorylation. As a result, T-bet expression is reduced as is the maturation of naive CD4+ cells into Th1 effectors. These changes indirectly support the generation of Th2-dominated immune responses. Suppressive ODN may thus represent a novel approach to influence the Th1:Th2 balance in vivo.

“…In this study, we use a novel approach for enhanced Ag uptake by B cells, that is, exposure of B cells to CpG-Ag conjugates. Basically, we took advantage of the previously described dual role of CpG-OVA complexes (14,15,20), that is, enhanced endocytosis via a sequence-nonspecific DNA receptor (15,17,32) as well as sequence-specific activation via endocytosed CpG-DNA that meets TLR9 at cytoplasmatic endosome-like organelles (28,29). This approach makes use of CpG-DNA as a vehicle for endocytosis of linked Ag and, upon endocytosis, as activator of Ag-loaded cells.…”

Section: Discussionmentioning

confidence: 99%

“…In this system, the function of Toll-like receptor 9 (TLR9) is restricted to the activation of immature DCs into professional APCs, while cross-presenting OVA. However, TLR9 is not involved in CpG-DNA-aided cellular uptake (15,17).…”

mentioning

confidence: 99%

CpG-DNA Aided Cross-Priming by Cross-Presenting B Cells

Heit

Huster

Schmitz

et al. 2004

127

109

Covalent linkage of immunostimulatory CpG-DNA to OVA (CpG-OVA complex) results in CpG-DNA-aided cross-presentation of OVA by dendritic cells (DCs). In this study, we analyzed the thesis that CpG-OVA complexes may be cross-presented by B cells to route internalized Ag into the class I MHC presentation pathway. First, we describe that conjugation of CpG-DNA to OVA enhances up to 40-fold internalization of OVA by B cells, which in turn generate the CD8 T cell epitope SIINFEKL complexed to MHC class I, albeit less efficiently than DCs. Furthermore, upon internalization, CpG-DNA conjugated to OVA stimulates B cells to up-regulate costimulatory molecules and cytokines including IL-12. Adoptive transfer of CpG-OVA complex-loaded wild-type B cells cross-primes naive CD8 T cells both in wild-type mice and in MyD88-deficient mice. Overall, these findings disclose attributes of B cells, including cross-presentation of exogenous Ag and cross-priming of naive CD8 T cells that hitherto have been considered as hallmarks restricted to DCs.