Differentiation of Inflammatory Dendritic Cells Is Mediated by NF-κB1–Dependent GM-CSF Production in CD4 T Cells

Abstract

Rel/NF-κB transcription factors regulate inflammatory and immune responses. Despite possible subunit redundancy, NF-κB1–deficient (Nfkb1−/−) mice were profoundly protected from sterile CD4 T cell-dependent acute inflammatory arthritis and peritonitis. We evaluated CD4 T cell function in Nfkb1−/− mice and found increased apoptosis and selectively reduced GM-CSF production. Apoptosis was blocked by expression of a Bcl-2 transgene without restoring a disease response. In contrast with wild-type cells, transfer of Nfkb1−/− or GM-CSF–deficient CD4 T cells into RAG-1–deficient (Rag1−/−) mice failed to support arthritis induction. Injection of GM-CSF into Nfkb1−/− mice fully restored the disease response, suggesting that T cells are an important source of GM-CSF during acute inflammation. In Ag-induced peritonitis, NF-κB1–dependent GM-CSF production in CD4 T cells was required for disease and for generation of inflammatory monocyte-derived dendritic cells (MoDC), but not conventional dendritic cells. MoDC were identified in inflamed synovium and draining lymph nodes during arthritis. These MoDC produced high levels of MCP-1, a potent chemoattractant for monocytes. This study revealed two important findings: NF-κB1 serves a critical role in the production of GM-CSF by activated CD4 T cells during inflammatory responses, and GM-CSF derived from these cells drives the generation of MoDC during inflammatory disease.

Foxp3-independent mechanism by which TGF-β controls peripheral T cell tolerance

“…The pathogenic monocyte response in Tgfbr2 −/− OT-II RIP-mOva mice is in part dependent on GM-CSF, a cytokine with established roles in myeloid cell homeostasis and monocyte activation (40)(41)(42)(43). GM-CSF also promotes the development of autoimmune diseases such as arthritis and EAE (45,46,59,60), both of which are associated with pathogenic myeloid cell responses (36,37,61). Indeed, GM-CSF signaling has been demonstrated to trigger an inflammatory signature in monocytes that contributes to their pathogenic function in autoimmunity (62).…”

“…Indeed, GM-CSF signaling has been demonstrated to trigger an inflammatory signature in monocytes that contributes to their pathogenic function in autoimmunity (62). However, the direct activation of innate immune cells through pattern-recognition receptors is another plausible pathogenic mechanism in the adjuvant-based models (45,46,59,62). In contrast, our findings demonstrate that in a spontaneous, non-adjuvant-based model of autoimmunity a dysregulated T cell response in a setting of sterile inflammation is sufficient to induce a pathogenic myeloid cell population that critically contributes to disease development.…”

Les cellules dendritiques inflammatoires

“…[6][7][8], levures ou parasites [9,10]. C'est également le cas dans des modèles d'inflammation expérimentale en l'absence de pathogène [11][12][13][14][15] ou encore dans des modèles de maladies inflammatoires (asthme, colite, arthrite rhumatoïde, sclérose en plaques) [6,[16][17][18] (Figure 1). Différents groupes ont ainsi montré que, lors d'une inflammation, des monocytes injectés à des souris se différenciaient en cellules dendritiques inflammatoires [4,6,9,12,19].…”

Functional regulation of monocyte-derived dendritic cells by microRNAs

“…By exhibiting these potent functions, moDCs offer a protective immunity role as well as mediate immunopathology (Aldridge et al, 2009). In autoimmune inflammation, moDCs are likely to be the major mediators of pathology (Campbell et al, 2011).…”

“…Despite that GM-CSF is a potent cytokine differentiating DCs from monocytes, how critical GM-CSF is for in vivo differentiation of moDCs is less clear. At least, in some mouse models, GM-CSF is believed to positively regulate the in vivo production of moDCs (Naik et al, 2006;Campbell et al, 2011). However, in response to acute infection like systemic infection with Listeria monocytogenes, recruitment /maturation of Ly6c + moDCs was not obviously hampered in the Gm-csf -/-mice (Zhan et al, 2012).…”