TLR agonists induce regulatory dendritic cells to recruit Th1 cells via preferential IP-10 secretion and inhibit Th1 proliferation

Abstract

IntroductionDendritic cells (DCs), the most potent professional antigenpresenting cells (APCs), are critical sentinels in antimicrobial immune responses with the unique ability to integrate a wide array of incoming signals and convey them to lymphocytes, directing the appropriate immune responses. 1,2 It is well known that immature DCs (imDCs) undergo maturation on recognition of pathogenic components via Toll-like receptors (TLRs), which enable DCs to produce different profiles of cytokines and chemokines and control the development of Th1/Th2-type adaptive immune responses. 3,4 In recent years, more and more studies have shown that DCs have the ability to down-regulate an immune response or induce immune tolerance. The ability of DCs to initiate an immune response or induce immune tolerance depends on their maturation state and different subsets. 5,6 Some kinds of regulatory DCs with negative regulatory functions have been reported, 7 and the regulatory DCs commonly used in most current work are prepared in vitro by culturing DC progenitors in the presence of immunosuppressive cytokines, such as IL-10 and TGF-␤. 8,9 However, how regulatory DCs will respond to TLR agonists and the roles of regulatory DCs triggered by TLR agonists in the control of Th1/Th2-type adaptive immune responses remain to be fully understood. Furthermore, the chemokine production in regulatory DCs has not yet been identified.Mature DCs (maDCs) are usually considered to be terminally differentiated and undergo activation-induced apoptosis. 10,11 However, our previous study demonstrated that spleen stromal cells, which mimic the secondary lymph organ microenvironment, can drive maDCs to proliferate and further differentiate into a unique form of regulatory DC subset (diffDCs), which express a higher level of IL-10 but minimal IL-12p70 and inhibit the proliferation of naïve CD4 ϩ T cells in response to antigen presented by maDCs. 12 Regulatory diffDCs can proliferate in response to antigen stimulation, thus exerting negative feedback control of the T-cell immune response in the late period of the immune response. In addition, endothelial splenic stroma may physiologically induce such regulatory DC differentiation from hematopoietic stem cells. 13 Chemokines are important mediators in the activation of innate and adaptive immunity and also in the regulation of inflammation and immune responses. 14 TLRs can sense microbial products and trigger maturation of DCs and chemokine production. Therefore, to better understand the functions of the regulatory DCs in inflammation and immune regulation, we investigated the chemokine expression pattern of the regulatory DCs with or without stimulation by TLR agonists, and then the sequence of the increased chemokine production by the TLR signaling-triggered regulatory DCs in the chemoattraction and regulation of T cells. We found that the regulatory DCs spontaneously secrete CXCR3 chemokine interferon-␥-inducible protein 10 (IP-10) and will produce much more IP-10 in response to TLR-2, -3, -4, and -9 agon...

Antigen‐specific suppression of established arthritis in mice by dendritic cells deficient in NF‐κB

“…Although T cells with a typical Tr1 phenotype from draining lymph nodes of mice given BAY 11-7082-treated DCs were unable to suppress mBSA-specific responses in vitro, it is possible that the induction conditions, migration to sites of pathology, or the presence of proinflammatory cytokines prevented suppression in this assay (31). The speed and antigen-specificity of the clinical response to BAY 11-7082-treated DCs suggest that these DCs rapidly alter the response of existing mBSA-specific immune effector T cells to a Tr1 phenotype, rather than induce Treg cells from naive precursors, very likely as a result of a collaborative interaction with constitutive FoxP3ϩ Treg cells and innate immune effectors, including NK cells, NK T cells, and macrophages (32)(33)(34).…”

TLR ligand suppression or enhancement of Treg cells? A double-edged sword in immunity to tumours

“…Therefore, TLR-activated Treg cells appear to be capable of enhancing the tolerogenic effect of DCs. Furthermore, stimulation of regulatory DCs with TLR2, TLR3, TLR4 or TLR9 agonists induces IP-10 production, which recruits Th1 cells, but inhibits proliferation of the recruited cells (Qian et al, 2007). CpG also induces Cox-2 and PGE2 expression in murine macrophages and spleen cells, and inhibition of Cox-2 enhanced serum levels of IFN-g in response to injection with CpG (Chen et al, 2001).…”

Innate Immunity in the Respiratory Epithelium

“…The CXCR3 ligands CXCL9 (MIG), CXCL10 (IP-10), and CXCL11 (I-TAC) provide a mechanism for epithelial and other resident cells to recruit T cells (122)(123)(124)(125)(126)(127)(128). The production of CXCR3 chemokines such as CXCL10 preferentially attracts Th1 T cells (Figure 1) (127,129) while antagonizing the recruitment of Th2 T cells (126).…”