Interleukin-7 regulates adipose tissue mass and insulin sensitivity in high-fat diet-fed mice through lymphocyte-dependent and independent mechanisms.

Although interleukin (IL)-7 is mostly known as a key regulator of lymphocyte homeostasis, we recently demonstrated that it also contributes to body weight regulation through a hypothalamic control. Previous studies have shown that IL-7 is produced by the human obese white adipose tissue (WAT) yet its potential role on WAT development and function in obesity remains unknown. Here, we first show that transgenic mice overexpressing IL-7 have reduced adipose tissue mass associated with glucose and insulin resistance. Moreover, in the high-fat diet (HFD)-induced obesity model, a single administration of IL-7 to C57BL/6 mice is sufficient to prevent HFD-induced WAT mass increase and glucose intolerance. This metabolic protective effect is accompanied by a significant decreased inflammation in WAT. In lymphocyte-deficient HFD-fed SCID mice, IL-7 injection still protects from WAT mass gain. However, IL-7-triggered resistance against WAT inflammation and glucose intolerance is lost in SCID mice. These results suggest that IL-7 regulates adipose tissue mass through a lymphocyte-independent mechanism while its protective role on glucose homeostasis would be relayed by immune cells that participate to WAT inflammation. Our observations establish a key role for IL-7 in the complex mechanisms by which immune mediators modulate metabolic functions.

Subcutaneous graft of D1 mouse mesenchymal stem cells leads to the formation of a bone-like structure.

Mesenchymal stem cells (MSC) are capable of both self-renewal and multi-lineage differentiation into mesoderm-type cells such as osteoblasts, chondrocytes, adipocytes and myocytes. Together the multipotent nature of MSCs and the facility to expand them in vitro make these cells ideal resources for regenerative medicine, particularly for bone reconstruction, and therefore research efforts focused on defining efficient protocols for directing their differentiation into the requisite lineage. Despite much progress in identifying mechanisms and factors that direct and control in vitro osteogenic differentiation of MSCs, a rapid and simple model to evaluate in vivo tissue formation is still lacking. Here, we describe the unique capacity of the murine bone marrow-derived D1 MSC cell line, which differentiates in vitro into at least three cell lineages, to form in vivo a structure resembling bone. This bone-like structure was obtained after subcutaneous grafting of D1 cells into immunocompetent mice without the need of neither an osteogenic factor nor scaffold material. These data allow us to propose this cell model as a tool for exploring in vivo the mechanisms and/or factors that govern and potentially regulate osteogenesis.

Feeding our immune system: impact on metabolism.

Endogenous intestinal microflora and environmental factors, such as diet, play a central role in immune homeostasis and reactivity. In addition, microflora and diet both influence body weight and insulin-resistance, notably through an action on adipose cells. Moreover, it is known since a long time that any disturbance in metabolism, like obesity, is associated with immune alteration, for example, inflammation. The purpose of this review is to provide an update on how nutrients-derived factors (mostly focusing on fatty acids and glucose) impact the innate and acquired immune systems, including the gut immune system and its associated bacterial flora. We will try to show the reader how the highly energy-demanding immune cells use glucose as a main source of fuel in a way similar to that of insulin-responsive adipose tissue and how Toll-like receptors (TLRs) of the innate immune system, which are found on immune cells, intestinal cells, and adipocytes, are presently viewed as essential actors in the complex balance ensuring bodily immune and metabolic health. Understanding more about these links will surely help to study and understand in a more fundamental way the common observation that eating healthy will keep you and your immune system healthy.

Presence of HIV-1 Nef specific CD4 T cell response is associated with non-progression in HIV-1 infection.

The ex vivo response to three HLA-DR-restricted Nef peptides (Nef 66-97, Nef 133-159, Nef 180-202) and one HLA-DQ-restricted Nef peptide (Nef 56-68) was evaluated in 28 HIV-seropositive patients and 6 Long-term Non-Progressors (LTNPs). Analyzing specific proliferative response and IFN-gamma secretion, patients were identified as high responders, medium responders and non-responders to peptides. As high responder patients, LTNP patients showed strong proliferative response to all the Nef-peptides as strong IFN-gamma secretion. Twenty-four months later, all high responder patients were always without antiretroviral treatment whereas 50% of medium responders and at least 66% of low responder patients followed bi-therapy. CDC classification confirmed also unfavourable evolution for these two last groups. All high responder patients conserved stable CD4 counts, proliferative response to Nef peptides as strong IFN-gamma secretion during this 24-month period. So, early good T CD4 response to peptides of the Nef protein could thus be regarded as a factor of good prognosis in HIV infection and a tool of importance in the decision to put or not a patient under treatment.

Impairment of dendritic cell functionality and steady-state number in obese mice.

There is a finely tuned interplay between immune and neuroendocrine systems. Metabolic disturbances like obesity will have serious consequences on immunity both at the cellular and at the cytokine expression levels. Our in vivo results confirm the immune deficiency of ob/ob mice, leptin deficient and massively obese, characterized by a reduced Ag-specific T cell proliferation after keyhole limpet hemocyanin immunization. In this report, we show that dendritic cells (DCs), major APCs involved in T lymphocyte priming, are affected in obese mice. Both their function and their steady-state number are disturbed. We demonstrate that DCs from ob/ob mice are less potent in stimulation of allogenic T cells in vitro. This impaired functionality is not associated with altered expression of phenotypic markers but with the secretion of immunosuppressive cytokines such as TGF-beta. Moreover, we show increased in vivo steady-state number of epidermal DCs in ob/ob mice, which is not due to a migratory defect. The ob/ob mice are characterized by the absence of functional leptin, a key adipokine linking nutrition, metabolism, and immune functions. Interestingly, intradermal injection of leptin is able to restore epidermal DC number in obese mice. Thus, DCs might be directly sensitive to metabolic disturbances, providing a partial explanation of the immunodeficiency associated with obesity.

Tetracycline-inducible viral interleukin-10 intraocular gene transfer, using adeno-associated virus in experimental autoimmune uveoretinitis.

Members of the adeno-associated virus (AAV) family are good candidates for the treatment of ocular diseases because of their relative lack of pathogenicity. We studied the effect of intraocular injection of AAV2-viral IL-10 (vIL-10) on retinal S-antigen-induced experimental autoimmune uveoretinitis (EAU) in Lewis rats. We demonstrated that AAV2/2-GFP injected into the vitreous body transduced the iris and ciliary body, or anterior uvea, and the retina. We showed that intravitreal injection of the AAV2/2-tetON-vIL-10 construct achieved detectable levels of vIL-10 mRNA and protein within the eye and was effective in protecting the rat retina against destruction. This protection was dependent on the level of vIL-10 present in the aqueous humor/ vitreous body. Intravitreal injection of the same construct encased within an AAV5 shell, AAV2/5-tetONvIL- 10, did not confer any degree of protection. It appeared that the AAV2/5 vectors did not transduce the anterior uvea, the site at which inflammatory cells first localize in EAU, nor the ganglion cell layer; induced low expression of vIL-10 mRNA; and did not achieve detectable levels of transgene expression in the aqueous humor/vitreous body. Local treatment with AAV2/2-tetON-vIL-10 did not dampen the systemic immune response, as determined by S-antigen-specific lymphocyte proliferation. Our results show that local intravitreal injection of AAV2/2 is an effective means by which to deliver immunoregulatory molecules into the eye during uveitis, a chronic human ocular disease.