IntroductionRegulatory T cells (Tregs), characterized by high expression of FoxP3, are potent immunomodulators of T-cell activation that suppress proliferation and cytokine secretion by effector T cells. [1][2][3][4][5] Loss of Tregs by either gene deletion of FoxP3 in mice or mutations in humans results in autoimmune disease and the inability to effectively regulate T-cell activation. 6,7 While Tregs play a fundamental role in protection of autoimmunity, their differentiation is tightly linked to the development of IL-17-producing (Th17) cells, a highly pathogenic effector T-cell subset involved in inducing inflammation and autoimmune tissue injury. 8,9 Both loss of Treg function and induction of Th17 cells have been implicated in the pathogenesis of human autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, Crohn disease, and psoriasis. [10][11][12][13][14] Although Tregs appear to be central in regulating immune responses to self-antigens, mechanisms must be present to rapidly block their suppressive activity and enable immune activation during an acute microbial infection. In such circumstances, antigen-presenting cells (APC) secrete inflammatory cytokines, such as interleukin-1␤ (IL-1␤) and IL-6, which induce the potent effector responses necessary to clear the infection. In this regard, our data and the work of others have demonstrated that IL-1␤ and IL-6 can drive memory CD4 ϩ T cells to secrete 16 , which has been shown to abrogate suppression by Treg cells, 17 also drives Th17 differentiation in naive cells when paired with transforming growth factor ␤ (TGF␤) in mouse 18 or with IL-1␤, interleukin-23 (IL-23), and TGF␤ in human, 19 although the minimal requirements for Th17 differentiation in human are still being defined. 15,[20][21][22] The role of TGF␤ in Th17 development is surprising, given that TGF␤ promotes adaptive Treg differentiation in murine models and enhances FoxP3 expression in the human system. 23 Yet recent studies in mouse have indicated that TGF␤ and IL-6 can induce IL-17 production in Tregs. 24,25 Despite the apparent duality in Treg/Th17 function, it is becoming increasingly clear that these cell subsets share common cytokine signaling pathways.The memory CD4 ϩ CD25 high human Treg lineage can be subdivided into 2 functionally distinct subsets classified by expression of the major histocompatibility complex (MHC) class II dimer human leukocyte antigen-DR (HLA-DR). 26 DR ϩ Tregs do not enter into cell cycle with T-cell receptor (TCR) cross-linking and exhibit immediate contact-dependent suppressor function. In contrast, DR Ϫ Tregs can enter into cell cycle after activation, secrete the inhibitory cytokine interleukin-10 (IL-10) but not the effector cytokine interferon-␥ (IFN␥), and demonstrate delayed kinetics of suppression, requiring 4 to 5 days for maximal inhibition of proliferation of responder CD4 ϩ T cells. 26 We have previously reported that, in cocultures of human Tregs and responder T cells (Tresp) provided with strong TCR stimulation, the Tresp are refrac...

Heme oxygenase-1 (HO-1) is an intracellular enzyme that degrades heme and inhibits immune responses and inflammation in vivo. In most cell types, HO-1 is inducible by inflammatory stimuli and oxidative stress. Here we demonstrate that human monocyte-derived immature dendritic cells (iDCs) and several but not all freshly isolated rat splenic DC subsets and rat bone marrow-derived iDCs, spontaneously express HO-1. HO-1 expression drastically decreases during human and rat DC maturation induced in vitro. In IntroductionHeme oxygenases (HOs) are the rate-limiting intracellular enzymes that degrade heme to biliverdin, free divalent iron, and CO (for a review, see Otterbein and Choi 1 ). Three distinct HO enzymes have been identified: HO-1, HO-2, and HO-3. 1 HO-1 is a stress responsive gene whose expression is induced by a variety of stimuli including heme, heavy metals, inflammatory cytokines, and nitric oxide. 1 HO-1 is known for its cytoprotective effect against oxidative injuries and inflammation. 1 Induction of HO-1 expression by pharmacologic activators or gene transfer has had therapeutic effects in a variety of conditions or disorders involving the immune system, including transplantation and inflammatory disorders. [2][3][4][5][6][7][8] Biliverdin and its metabolite, bilirubin, are known for their antioxidant 9 and immunosuppressive effects. 10 HO-1 and CO have been shown to inhibit lipopolysaccharide (LPS)-induced expression of proinflammatory cytokines and to increase LPS-induced expression of interleukin 10 (IL-10) in macrophages. 11,12 Moreover, IL-10 induces HO-1 expression in macrophages. [13][14][15] We previously reported that overexpression of HO-1, obtained with an HO-1-encoding adenovirus in rats having heart transplants, results in long-term allograft survival associated with an inhibition of cellular allogeneic immune responses, which could be mediated by adenoviral transduction of dendritic cells (DCs). 6 DCs play a central role in the induction of immunity and tolerance (for a review, see Steinman et al 16 ). In the absence of inflammation, immature DCs (iDCs) located in peripheral tissues specialize in taking up innocuous and cell-associated self antigens.They continuously capture antigens and migrate to draining lymph nodes where they can induce tolerance. 16 In the presence of danger signals, DCs undergo maturation, a process involving upregulation of surface major histocompatibility complex (MHC) class II and costimulatory molecules, secretion of proinflammatory and anti-inflammatory cytokines, and the acquired ability to stimulate differentiation of naive T cells into effector cells.Our working hypothesis was that DCs can express HO-1, which can regulate DC functions. In this study, we demonstrate that human and rat iDCs express HO-1 and that HO-1 expression is down-regulated by maturation stimuli. Our results also demonstrate that induction of HO-1 expression renders DCs refractory to LPS-induced maturation, but preserves IL-10 secretion, suggesting that HO-1 may be used to regulate DC f...

IL-22 is mainly produced at barrier surfaces by T cells and innate lymphoid cells and is crucial to maintain epithelial integrity. However, dysregulated IL-22 action leads to deleterious inflammation and is involved in diseases such as psoriasis, intestinal inflammation and cancer. IL-22BP is a soluble inhibitory IL-22 receptor and may represent a crucial regulator of IL-22. We show both in rats and mice that, in the steady state, the main source of IL-22BP is constituted by a subset of conventional dendritic cells (DC) in lymphoid and non lymphoid tissues. In mouse intestine, IL-22BP was specifically expressed in lamina propria CD103+CD11b+ DC. In humans, IL-22BP was expressed in immature monocyte-derived DC (MDDC) and strongly induced by retinoic acid (RA) but dramatically reduced upon maturation. Our data suggest that a subset of immature DC may actively participate in the regulation of IL-22 activity in the gut by producing high levels of IL-22BP.