Follicular dendritic cells control engulfment of apoptotic bodies by secreting Mfge8

The secreted phosphatidylserine-binding protein milk fat globule epidermal growth factor 8 (Mfge8) mediates engulfment of apoptotic germinal center B cells by tingible-body macrophages (TBMφs). Impairment of this process can contribute to autoimmunity. We show that Mfge8 is identical to the mouse follicular dendritic cell (FDC) marker FDC-M1. In bone-marrow chimeras between wild-type and Mfge8−/− mice, all splenic Mfge8 was derived from FDCs rather than TBMφs. However, Mfge8−/− TBMφs acquired and displayed Mfge8 only when embedded in Mfge8+/+ stroma, or when situated in lymph nodes draining exogenous recombinant Mfge8. These findings indicate a licensing role for FDCs in TBMφ-mediated removal of excess B cells. Lymphotoxin-deficient mice lacked FDCs and splenic Mfge8, and suffer from autoimmunity similar to Mfge8−/− mice. Hence, FDCs facilitate TBMφ-mediated corpse removal, and their malfunction may be involved in autoimmunity

FoxP3+ regulatory T cells essentially contribute to peripheral CD8+ T-cell tolerance induced by steady-state dendritic cells

Peripheral T-cell tolerance is thought to significantly contribute to the prevention of autoimmunity, and it has been shown that antigen-presenting steady-state dendritic cells efficiently induce peripheral tolerance. We previously showed that dendritic-cell-induced tolerance is a T-cell-intrinsic process that depends on coinhibitory molecules such as programmed death-1. Here we specifically analyze the involvement of FoxP3(+) regulatory T cells, which are known to be important for maintenance of self-tolerance. We show that antigen presentation by steady-state dendritic cells failed to induce peripheral tolerance in the absence of FoxP3(+) regulatory T cells but induced protective CD8(+) T-cell-mediated immunity instead. Regulatory T-cell-depleted mice had massively increased numbers of dendritic cells in lymph nodes. Dendritic cells isolated from mice without regulatory T cells had up-regulated costimulatory molecules and showed stronger T-cell stimulatory capacity ex vivo, suggesting that regulatory T cells contribute to peripheral tolerance by keeping the dendritic cells in an immature state. Using blocking antibodies, we demonstrate that CTLA-4 but not IL-10 is necessary for control of dendritic cells by regulatory T cells

Deletion of Fas in adipocytes relieves adipose tissue inflammation and hepatic manifestations of obesity in mice

Adipose tissue inflammation is linked to the pathogenesis of insulin resistance. In addition to exerting death-promoting effects, the death receptor Fas (also known as CD95) can activate inflammatory pathways in several cell lines and tissues, although little is known about the metabolic consequence of Fas activation in adipose tissue. We therefore sought to investigate the contribution of Fas in adipocytes to obesity-associated metabolic dysregulation. Fas expression was markedly increased in the adipocytes of common genetic and diet-induced mouse models of obesity and insulin resistance, as well as in the adipose tissue of obese and type 2 diabetic patients. Mice with Fas deficiency either in all cells or specifically in adipocytes (the latter are referred to herein as AFasKO mice) were protected from deterioration of glucose homeostasis induced by high-fat diet (HFD). Adipocytes in AFasKO mice were more insulin sensitive than those in wild-type mice, and mRNA levels of proinflammatory factors were reduced in white adipose tissue. Moreover, AFasKO mice were protected against hepatic steatosis and were more insulin sensitive, both at the whole-body level and in the liver. Thus, Fas in adipocytes contributes to adipose tissue inflammation, hepatic steatosis, and insulin resistance induced by obesity and may constitute a potential therapeutic target for the treatment of insulin resistance and type 2 diabetes

Current knowledge on exocrine glands in carabid beetles: structure, function and chemical compounds

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(A) Apoptotic cells, TBMφs, and GCs were visualized by TUNEL, anti-CD68, and PNA, respectively, on splenic cryosections 9 wk after BM reconstitution and after immunization

(right) Each datapoint represents the mean number of TUNEL cells per TBMφ in one individual GC. → and WT→ mice showed increased numbers of TUNEL cells per TBMφ. Horizontal bars represent means. White circles (left) indicate GCs. Bars, 100 μm. (B) Ultrastructural features of TBMφs of aged BM-chimeric mice 41 wk after reconstitution. Apoptotic cells in various degradation stages were observed inside TBMφs of all chimeric mice. (C) Engulfment of apoptotic cells by TBMφs in WT, , , , and mice was analyzed by TUNEL (green) and CD68 (red) staining. WT TBMφs contained copious TUNEL material. The latter was also observed in mice, but most TUNEL cells were large and intact. , , and macrophages were small and only contained intact TUNEL cells. At least three mice per genotype and ≥10 follicles per mouse were analyzed. Bars, 20 μm.<p><b>Copyright information:</b></p><p>Taken from "Follicular dendritic cells control engulfment of apoptotic bodies by secreting Mfge8"</p><p></p><p>The Journal of Experimental Medicine 2008;205(6):1293-1302.</p><p>Published online 9 Jun 2008</p><p>PMCID:PMC2413028.</p><p></p