Involvement of suppressors of cytokine signaling in toll-like receptor–mediated block of dendritic cell differentiation

Abstract

IntroductionInnate immunity represents the first line of defense against invading pathogens. Tissue-resident immune cells, including macrophages and dendritic cells (DCs), are the first immune cells to encounter infectious agents. Recognition of infecting pathogens within these cells is performed by now well-known pattern recognition receptors responding to conserved microbial structures. 1 Among these receptors, toll-like receptors (TLRs) have been identified as playing a pivotal role and indeed, both macrophages and dendritic cells express TLRs. [2][3][4] In macrophages, TLR stimulation activates the antimicrobial weaponry, including increased phagocytosis 5 ; in dendritic cells, migration into lymph nodes, antigen presentation, cytokine secretion, and subsequent activation of adaptive immunity 6 are enhanced. Interestingly, both of these primary pathogen-encountering cells can develop from monocytes, which thus serve as common progenitors. Differentiation is regulated by cytokines from the environment and immune cells among which macrophage colony-stimulating factor (M-CSF) and granulocyte-macrophagecolony-stimulating factor (GM-CSF) are of ultimate importance.Although it is well accepted that TLR stimulation activates macrophages and dendritic cells, there is only limited information as to a role of TLRs during differentiation processes. Thus, it is largely unknown whether TLR stimulation affects the replenishment of tissue-resident macrophages and dendritic cells from monocytes. This question is of significance as it might suggest a role for infectious stimuli to influence and guide the cellular composition of inflammatory responses.It has been reported that migration of dendritic cells from local tissue to lymph nodes can be inhibited by intradermal administration of either whole Salmonella typhimurium or simply by LPS in a TLR-4-dependent manner. 7 Another study showed that administration of LPS during the early stage of differentiation of human monocytes to DCs diminished the generation of CD1a ϩ DCs. 8 This was confirmed by another group demonstrating that this blocking effect of LPS depends on activation of mitogen-activated protein kinase p38. 9 However, the exact mechanisms of these inhibitory effects still remain to be identified. Secreted cytokines such as IL-10 9 have been suggested but seem to play only a minor role. 7 Myeloid dendritic cell differentiation depends on the activity of GM-CSF, a cytokine that signals through Janus kinases (JAKs) and signal transducers and activators of transcription (STATs), especially JAK2 and STAT5. 10 Suppressor of cytokine signaling proteins (SOCS) have been identified as intracellular feedback inhibitors of JAK/STAT signaling. 11-13 Furthermore, SOCS-1 has been shown to negatively regulate JAK2 and GM-CSF signaling by inhibiting phosphorylation 14 as well as proteasomal targeting 15 of JAK2. Accordingly, SOCS-1 knockout mice, in spite of a lethal phenotype due to hypersensitivity 16,17 toward IFN-␥, also exhibit hyperresponsiveness to GM-CSF. 18,19 We and othe...

PD‐L1 expression on tolerogenic APCs is controlled by STAT‐3

“…When isolated CD14 1 monocytes were stimulated with in the presence of LPS, cells failed to upregulate the DC marker CD1a and retained CD14 expression [5], which contrasts the phenotype obtained with G4 stimulation alone. When we tested other TLR agonists, we found that the TLR7/8 small molecular weight agonist R848 influences the differentiation of DCs in a comparable manner (Fig.…”

“…The effect on CD11c could be traced back to a SOCS-1 dependent blockade of STAT-5 phosphorylation. Additionally, we could show that SOCS-3 is also able to reduce STAT-5 phosphorylation [5]. Since TLR-APC upregulate preferentially SOCS3 (data not shown) we suppose that in the human system the block of STAT-5 might be SOCS-3-dependent.…”

“…It has been shown that encounter of monocytes with LPS during the very beginning of the differentiation process blocks conventional differentiation to iDCs. A phenotypically distinct APC type (TLR-APC) is generated, characterized by a [5][6][7]. Activation of p38 MAPK, the secretion of IL-10 and the inactivation of ERK and NF-kB [7] have been correlated with the generation of TLR-APCs.…”

A Suppressor of Cytokine Signaling 1 Antagonist Enhances Antigen-Presenting Capacity and Tumor Cell Antigen-Specific Cytotoxic T Lymphocyte Responses by Human Monocyte-Derived Dendritic Cells

“…GM-CSF is an essential factor in the generation of DCs. Although signaling through TLRs induced the maturation of DCs from iDCs, it suppressed GM-CSF-mediated DC development from CD14 ϩ human monocytes (18). SOCS1 was shown to be involved in this process, as SOCS1 was highly upregulated by TLR signals, thereby suppressing GM-CSF signals.…”

“…SOCS1, a member of the SOCS and cytokine-induced Src homology 2 (SH2) protein (CIS) family of intracellular proteins, has emerged as a critical inhibitory molecule for controlling the cytokine response and antigen presentation by DCs, thereby regulating the magnitude of adaptive immunity (14)(15)(16)(17)(18)(19). It has been reported that DCs from SOCS1 knockout mice (SOCS1 Ϫ/Ϫ DCs) were hypersensitive to lipopolysaccharide (LPS) stimulation and exhibited a more mature phenotype than DCs from their wildtype littermates (14).…”