Insulin inhibits IL-10-mediated regulatory T cell function: implications for obesity.

Chronic inflammation is known to promote metabolic dysregulation in obesity and type 2 diabetes. Although the precise origin of the unchecked inflammatory response in obesity is unclear, it is known that overproduction of proinflammatory cytokines by innate immune cells affects metabolism. For example, TNF-α contributes to the inability of cells to respond to insulin and to the increase in levels of insulin. Whether this hyperinsulinemia itself is part of a feedback loop that affects the progression of chronic adipose inflammation is unknown. In this article, we show that regulatory T cells (Tregs) express the insulin receptor, and that high levels of insulin impair the ability of Tregs to suppress inflammatory responses via effects on the AKT/mTOR signaling pathway. Insulin activated AKT signaling in Tregs, leading to inhibition of both IL-10 production and the ability of Tregs to suppress the production of TNF-α by macrophages in a contact-independent manner. The effect of insulin on Treg suppression was limited to IL-10 production and it did not alter the expression of other proteins associated with Treg function, including CTLA-4, CD39, and TGF-ß. In a model of diet-induced obesity, Tregs from the visceral adipose tissue of hyperinsulinemic, obese mice showed a similar specific decrease in IL-10 production, as well as a parallel increase in production of IFN-γ. These data suggest that hyperinsulinemia may contribute to the development of obesity-associated inflammation via a previously unknown effect of insulin on the IL-10-mediated function of Tregs.

Cutting edge: PHLPP regulates the development, function, and molecular signaling pathways of regulatory T cells.

Regulatory T cells (Tregs) have a reduced capacity to activate the PI3K/Akt pathway downstream of the TCR, and the resulting low activity of Akt is necessary for their development and function. The molecular basis for the failure of Tregs to activate Akt efficiently, however, remains unknown. We show that PH-domain leucine-rich-repeat protein phosphatase (PHLPP), which dephosphorylates Akt, is upregulated in Tregs, thus suppressing Akt activation. Tregs expressed higher levels of PHLPP than those of conventional T cells, and knockdown of PHLPP1 restored TCR-mediated activation of Akt in Tregs. Consistent with their high Akt activity, the suppressive capacity of Tregs from PHLPP1(-/-) mice was significantly reduced. Moreover, the development of induced Tregs was impaired in PHLPP1(-/-) mice. The increased level of Akt's negative regulator, PHLPP, provides a novel mechanism used by T cells to control the Akt pathway and the first evidence, to our knowledge, for a molecular mechanism underlying the functionally essential reduction of Akt activity in Tregs.

Active vitamin D (1,25-dihydroxyvitamin D3) increases host susceptibility to Citrobacter rodentium by suppressing mucosal Th17 responses.

Vitamin D deficiency affects more that 1 billion people worldwide and is associated with an increased risk of developing a number of inflammatory/autoimmune diseases, including inflammatory bowel disease (IBD). At present, the basis for the impact of vitamin D on IBD and mucosal immune responses is unclear; however, IBD is known to reflect exaggerated immune responses to luminal bacteria, and vitamin D has been shown to play a role in regulating bacteria-host interactions. Therefore, to test the effect of active vitamin D on host responses to enteric bacteria, we gave 1,25(OH)(2)D(3) to mice infected with the bacterial pathogen Citrobacter rodentium, an extracellular microbe that causes acute colitis characterized by a strong Th1/Th17 immune response. 1,25(OH)(2)D(3) treatment of infected mice led to increased pathogen burdens and exaggerated tissue pathology. In association with their increased susceptibility, 1,25(OH)(2)D(3)-treated mice showed substantially reduced numbers of Th17 T cells within their infected colons, whereas only modest differences were noted in Th1 and Treg numbers. In accordance with the impaired Th17 responses, 1,25(OH)(2)D(3)-treated mice showed defects in their production of the antimicrobial peptide REG3γ. Taken together, these studies show that 1,25(OH)(2)D(3) suppresses Th17 T-cell responses in vivo and impairs mucosal host defense against an enteric bacterial pathogen.

SHIP regulates the reciprocal development of T regulatory and Th17 cells.

Maintaining an appropriate balance between subsets of CD4(+) Th and T regulatory cells (Tregs) is critical to maintain immune homeostasis and prevent autoimmunity. Through a common requirement for TGF-beta, the development of peripherally induced Tregs is intimately linked to that of Th17 cells, with the resulting lineages depending on the presence of proinflammatory cytokines such as IL-6. Currently very little is known about the molecular signaling pathways that control the development of Tregs vs Th17 cells. Reduced activity of the PI3K pathway is required for TGF-beta-mediated induction of Foxp3 expression and the suppressive activity of Tregs. To investigate how negative regulators of the PI3K pathway impact Treg development, we investigated whether SHIP, a lipid phosphatase that regulates PI3K activity, also plays a role in the development and function of Tregs. SHIP-deficient Tregs maintained suppressive capacity in vitro and in a T cell transfer model of colitis. Surprisingly, SHIP-deficient Th cells were significantly less able to cause colitis than were wild-type Th cells due to a profound deficiency in Th17 cell differentiation, both in vitro and in vivo. The inability of SHIP-deficient T cells to develop into Th17 cells was accompanied by decreased IL-6-stimulated phosphorylation of STAT3 and an increased capacity to differentiate into Treg cells under the influence of TGF-beta and retinoic acid. These data indicate that SHIP is essential for normal Th17 cell development and that this lipid phosphatase plays a key role in the reciprocal regulation of Tregs and Th17 cells.

A randomized study of adefovir dipivoxil in place of HBIG in combination with lamivudine as post-liver transplantation hepatitis B prophylaxis.

UNLABELLED: Prior to effective prophylaxis, liver transplantation for hepatitis B virus (HBV)-related disease was frequently complicated by recurrence, which could be severe and rapidly progressive. Combination hepatitis B immunoglobulin (HBIG) and lamivudine prophylaxis reduces this rate of recurrence to <5% at 5 years; however, HBIG administration is costly and inconvenient. We conducted a multicenter randomized study of adefovir dipivoxil substitution for low-dose intramuscular (IM) HBIG in patients without HBV recurrence at least 12 months posttransplantation for HBV-related disease. Thirty-four patients were randomized, 16 to adefovir (1 patient withdrew consent at 3 months and is not considered in the results) and 18 to continue HBIG. All continued lamivudine. Groups were well matched by age, sex, and time since transplantation (median, 4.5 years), and background virological risk for HBV recurrence (30% of patients in the adefovir group, 24% in the HBIG group having detectable HBV DNA at transplantation). All patients were alive at study completion without recurrence. One patient in the adefovir group became hepatitis B surface antigen-positive at 5 months but was persistently HBV DNA undetectable via polymerase chain reaction (sensitivity 14 IU/mL) over the following 20 months. Median creatinine was not significantly changed over the course of the study in either group. One patient in the adefovir group with a background of diabetic and hypertensive nephropathy (baseline creatinine 150 micromol/L) developed increased creatinine leading to dose reduction and ultimately cessation of adefovir at 15 months. Yearly cost of combination adefovir/lamivudine prophylaxis was $8,290 versus $13,718 IM HBIG/lamivudine. CONCLUSION: Compared with combination HBIG plus lamivudine prophylaxis, combination adefovir plus lamivudine provides equivalent protection against recurrent HBV infection but with better tolerability and less cost.

Post-liver transplant hepatitis B prophylaxis: the role of oral nucleos(t)ide analogues.

PURPOSE OF REVIEW: The established gold standard for prophylaxis against hepatitis B virus (HBV) recurrence post-liver transplant is combination hepatitis B immune globulin (HBIG) and lamivudine. This therapy reduces the risk of recurrence to less than 5% at 5 years; however, the cost of HBIG has led to the investigation of alternatives. This paper reviews the HBIG-sparing alternatives achieved with lamivudine and the prospects for the newer anti-HBV agents in post-liver transplant prophylaxis. RECENT FINDINGS: When used with lamivudine as part of combination prophylaxis, low-dose intramuscular HBIG is equivalent to high-dose intravenous HBIG. There is recent evidence that in patients receiving HBIG/lamivudine, HBIG can be replaced with adefovir dipivoxil at 6-12 months post-liver transplant without precipitating recurrence. Furthermore, a recent study showed that primary prophylaxis with combination adefovir/lamivudine therapy without the use of long-term HBIG was effective and well tolerated as primary prophylaxis. SUMMARY: Although there are few studies of potent newer anti-HBV agents such as entecavir or tenofovir being used as HBV prophylaxis, the properties of these drugs suggest that they should replace lamivudine within HBV prophylaxis regimes.

Liver transplantation for hepatitis B: what is the best hepatitis B immune globulin/antiviral regimen?

1. Prophylaxis using the combination of lamivudine and high-dose intravenous hepatitis B immunoglobulin (approximately 10,000 IU monthly) reduces the long-term risk of recurrence of hepatitis B in hepatitis B surface antigen-positive transplant recipients to 5% to 10%. However, this therapy is expensive and inconvenient for patients. 2. Recent studies have shown that similar results can be obtained, at far less cost, with much lower doses of intramuscular hepatitis B immune globulin (400-800 IU monthly) in combination with pretransplant and posttransplant lamivudine therapy. 3. The development of lamivudine resistance pre-transplant can lead to hepatic decompensation and increases the risk of posttransplant recurrence in patients receiving hepatitis B immune globulin/lamivudine prophylaxis. Newer nucleos(t)ide analogues with lower resistance rates such as entecavir, adefovir, and tenofovir should therefore replace lamivudine in hepatitis B prophylaxis. 4. Combination therapy with these newer agents and low-dose intramuscular hepatitis B immune globulin is likely to be the most cost effective hepatitis B immune globulin-containing regimen for the prevention of hepatitis B recurrence post-transplant. 5. Some form of hepatitis B virus prophylaxis needs be continued indefinitely post-transplant. However, the use of antivirals with very low rates of drug resistance will make it possible to stop hepatitis B immune globulin therapy in many patients currently receiving hepatitis B immune globulin/nucleos(t)ide combination therapy.

T regulatory cell chemokine production mediates pathogenic T cell attraction and suppression.

T regulatory cells (Tregs) control immune homeostasis by preventing inappropriate responses to self and nonharmful foreign antigens. Tregs use multiple mechanisms to control immune responses, all of which require these cells to be near their targets of suppression; however, it is not known how Treg-to-target proximity is controlled. Here, we found that Tregs attract CD4+ and CD8+ T cells by producing chemokines. Specifically, Tregs produced both CCL3 and CCL4 in response to stimulation, and production of these chemokines was critical for migration of target T cells, as Tregs from Ccl3-/- mice, which are also deficient for CCL4 production, did not promote migration. Moreover, CCR5 expression by target T cells was required for migration of these cells to supernatants conditioned by Tregs. Tregs deficient for expression of CCL3 and CCL4 were impaired in their ability to suppress experimental autoimmune encephalomyelitis or islet allograft rejection in murine models. Moreover, Tregs from subjects with established type 1 diabetes were impaired in their ability to produce CCL3 and CCL4. Together, these results demonstrate a previously unappreciated facet of Treg function and suggest that chemokine secretion by Tregs is a fundamental aspect of their therapeutic effect in autoimmunity and transplantation.

The Role of the PI3K Signaling Pathway in CD4(+) T Cell Differentiation and Function.

The relative activity of regulatory versus conventional CD4(+) T cells ultimately maintains the delicate balance between immune tolerance and inflammation. At the molecular level, the activity of phosphatidylinositol 3-kinase (PI3K) and its downstream positive and negative regulators has a major role in controlling the balance between immune regulation and activation of different subsets of effector CD4(+) T cells. In contrast to effector T cells which require activation of the PI3K to differentiate and mediate their effector function, regulatory T cells rely on minimal activation of this pathway to develop and maintain their characteristic phenotype, function, and metabolic state. In this review, we discuss the role of the PI3K signaling pathway in CD4(+) T cell differentiation and function, and focus on how modulation of this pathway in T cells can alter the outcome of an immune response, ultimately tipping the balance between tolerance and inflammation.