Active suppression is mediated by a subpopulation of CD4(+) T cells that prevents autoimmunity. However, the mechanisms involved in their differentiation in vivo are currently under intensive research. Here we show that in vitro culture of bone marrow cells in the presence of IL-10 induces the differentiation of a distinct subset of dendritic cells with a specific expression of CD45RB. These CD11c(low)CD45RB(high) DCs are present in the spleen and lymph nodes of normal mice and are significantly enriched in the spleen of IL-10 Tg mice. These natural or in vitro-derived DCs display plasmacytoid morphology and an immature-like phenotype, and secrete high levels of IL-10 after activation. OVA peptide-pulsed CD11c(low)CD45RB(high) DCs specifically induce tolerance through the differentiation of Tr1 cells in vitro and in vivo. Our findings identify a natural DC subset that induces the differentiation of Tr1 cells and suggest their therapeutic use.

T-cell regulation in adipose tissue provides a link between inflammation and insulin resistance. Because of alterations in adipose tissue T-cell composition in obesity, we aimed to identify the antigen-presenting cells in adipose tissue of obese mice and patients with insulin resistance. Dendritic cells (DCs) and T cells were studied in mice and in two cohorts of obese patients. In lean mice, only CD11c+ DCs were detected in adipose tissue. Adoptive transfer of naive CD4+ T cells in Rag1−/− mice led to a predominant Th1 response in adipose tissue. In contrast, during obesity DCs (human CD11c+CD1c+ and mouse CD11chighF4/80low) accumulated in adipose tissue. CD11chighF4/80low DCs from obese mice induced Th17 differentiation. In patients, the presence of CD11c+CD1c+ DCs correlated with the BMI and with an elevation in Th17 cells. In addition, these DCs led to ex vivo Th17 differentiation. CD1c gene expression further correlated with homeostatic model assessment-insulin resistance in the subcutaneous adipose tissue of obese patients. We show for the first time the presence and accumulation of specific DCs in adipose tissue in mouse and human obesity. These DCs were functional and could be important regulators of adipose tissue inflammation by regulating the switch toward Th17 cell responses in obesity-associated insulin resistance.

Osteoclasts (OCLs) are key players in controlling bone remodeling. Modifications in their differentiation or bone resorbing activity are associated with a number of pathologies ranging from osteopetrosis to osteoporosis, chronic inflammation and cancer, that are all characterized by immunological alterations. Therefore, the 2000s were marked by the emergence of osteoimmunology and by a growing number of studies focused on the control of OCL differentiation and function by the immune system. At the same time, it was discovered that OCLs are much more than bone resorbing cells. As monocytic lineage-derived cells, they belong to a family of cells that displays a wide heterogeneity and plasticity and that is involved in phagocytosis and innate immune responses. However, while OCLs have been extensively studied for their bone resorption capacity, their implication as immune cells was neglected for a long time. In recent years, new evidence pointed out that OCLs play important roles in the modulation of immune responses toward immune suppression or inflammation. They unlocked their capacity to modulate T cell activation, to efficiently process and present antigens as well as their ability to activate T cell responses in an antigen-dependent manner. Moreover, similar to other monocytic lineage cells such as macrophages, monocytes and dendritic cells, OCLs display a phenotypic and functional plasticity participating to their anti-inflammatory or pro-inflammatory effect depending on their cell origin and environment. This review will address this novel vision of the OCL, not only as a phagocyte specialized in bone resorption, but also as innate immune cell participating in the control of immune responses.

Bone destruction is a hallmark of chronic rheumatic diseases. Although the role of osteoclasts in bone loss is clearly established, their implication in the inflammatory response has not been investigated despite their monocytic origin. Moreover, specific markers are lacking to characterize osteoclasts generated in inflammatory conditions. Here, we have explored the phenotype of inflammatory osteoclasts and their effect on CD4 T cell responses in the context of bone destruction associated with inflammatory bowel disease. We used the well-characterized model of colitis induced by transfer of naive CD4 T cells into Rag1 mice, which is associated with severe bone destruction. We set up a novel procedure to sort pure osteoclasts generated in vitro to analyze their phenotype and specific immune responses by FACS and qPCR. We demonstrated that osteoclasts generated from colitic mice induced the emergence of TNFα-producing CD4 T cells, whereas those generated from healthy mice induced CD4 FoxP3 regulatory T cells, in an antigen-dependent manner. This difference is related to the osteoclast origin from monocytes or dendritic cells, to their cytokine expression pattern, and their environment. We identified CX CR1 as a marker of inflammatory osteoclasts and we demonstrated that the differentiation of CX CR1 osteoclasts is controlled by IL-17 in vitro. This work is the first demonstration that, in addition to participating to bone destruction, osteoclasts also induce immunogenic CD4 T cell responses upon inflammation. They highlight CX CR1 as a novel dual target for antiresorptive and anti-inflammatory treatment in inflammatory chronic diseases. © 2016 American Society for Bone and Mineral Research.

OBJECTIVE-Osteopontin (OPN) plays an important role in the development of insulin resistance and liver complications in dietary murine models. We aimed to determine the expression pattern of OPN and its receptor CD44 in obese patients and mice according to insulin resistance and liver steatosis.RESEARCH DESIGN AND METHODS-OPN and CD44 expressions were studied in 52 morbidly obese patients and in mice. Cellular studies were performed in HepG2 cells. RESULTS-HepaticOPN and CD44 expressions were strongly correlated with liver steatosis and insulin resistance in obese patients and mice. This increased OPN expression could be due to the accumulation of triglycerides, since fat loading in HepG2 promotes OPN expression. In contrast, OPN expression in adipose tissue (AT) was enhanced independently of insulin resistance and hepatic steatosis in obese patients. The elevated OPN expression in AT was paralleled with the AT macrophage infiltration, and both phenomena were reversed after weight loss. The circulating OPN level was slightly elevated in obese patients and was not related to liver steatosis. Further, AT did not appear to secrete OPN. In contrast, bariatric surgery-induced weight loss induced a strong increase in circulating OPN. CONCLUSIONS-The modestly elevated circulating OPN levels in morbidly obese patients were not related to liver steatosis and did not appear to result from adipose tissue secretion. In subcutaneous AT, expression of OPN was directly related to macrophage accumulation independently from liver complications. In contrast, hepatic OPN and CD44 expressions were related to insulin resistance and steatosis, suggesting their local implication in the progression of liver injury. Diabetes 58: 125-133, 2009

IntroductionAn increasing number of studies underline the interactions between the bone and immune systems and have led to the emergence of osteoimmunology. 1,2 Excessive bone resorption is frequently associated with chronic infections and autoimmune and inflammatory diseases. [3][4][5][6] The immune system plays a major role in this process, in particular through activated T cells, which secrete proinflammatory cytokines involved in osteoclastogenesis. 7 However, less is known about the involvement of other immune cells in the control of bone resorption. Dendritic cells (DCs) also play an important role in autoimmune and inflammatory diseases. 8 These cells derive from the same myeloid precursor as osteoclasts (OCLs), and both cell types are modulated by common factors, mainly by receptor activator of NF-B ligand (RANK-L). RANK-L is essential for the differentiation of OCLs, 9 the activity and survival of DCs. 10 These data highlight a potential link between DCs and OCLs.Cells from the myelomonocytic lineage, including DCs, display a high developmental and functional plasticity depending on local factors and stimuli experienced during their differentiation and maturation. 11,12 Although they were considered to be terminally differentiated cells, recent studies have suggested that mature splenic DCs can be influenced by their microenvironment to undergo further differentiation. Splenic stromal cells induce mature DCs to differentiate into regulatory DCs, which differ from mature DCs by their phenotype, their cytokine secretion pattern, and their ability to inhibit T-cell proliferation. 13 Moreover, DCs generated in vitro transdifferentiate into endothelial cells when cultured with tumor-conditioned media 14 or into OCLs when cultured with osteoclastogenic factors. 15,16 Although these in vitro studies revealed the capacity of DCs to transdifferentiate into other cell types under specific conditions, it is not clear yet whether this plasticity takes place in vivo.Osteopetrosis is characterized by an impaired bone resorption because of the absence of OCL formation or activity. 17 In the osteopetrotic oc/oc mouse, differentiated OCLs are present but are unable to resorb bone because of a deletion in the Tcirg1 gene encoding the a3 subunit of the vacuolar ATPase. 18 The a3 protein is responsible for the acidification process necessary for the dissolution of the bone matrix leading to the formation of resorption lacunae. In the absence of a3 expression, the bone marrow of oc/oc mice is filled with numerous and disorganized trabeculae, and osteoclastogenesis is highly increased. 19,20 The consequence of this severe osteopetrotic phenotype is a life span less than 3 weeks. Therefore, the oc/oc mouse provides an appropriate model to assess the in vivo capacity of wild-type precursor cells to give rise to functional OCLs.To assess whether DCs have an osteoclastogenic potential, we purified them from normal mice and cultured them with RANK-L and macrophage-colony stimulating factor (M-CSF). We showed that this treatment a...

Our results highlight the osteoclastogenic function of the Th17 TNF-α(+) cells that contribute to bone loss in vivo in IBD.

Osteoclasts promote the formation of the HSC niche by inducing the differentiation of osteoblastic cells from mesenchymal stem cells.