Vitamin A is a multifunctional vitamin implicated in a wide range of biological processes. Its control over the immune system and functions are perhaps the most pleiotropic not only for development ...but also for the functional fate of almost every cell involved in protective or regulatory adaptive or innate immunity. This is especially key at the intestinal border, where dietary vitamin A is first absorbed. Most effects of vitamin A are exerted by its metabolite, retinoic acid (RA), which through ligation of nuclear receptors controls transcriptional expression of RA target genes. In addition to this canonical function, RA and RA receptors (RARs), either as ligand-receptor or separately, play extranuclear, nongenomic roles that greatly expand the multiple mechanisms employed for their numerous and paradoxical functions that ultimately link environmental sensing with immune cell fate. This review discusses RA and RARs and their complex roles in innate and adaptive immunity.
The intraepithelial lymphocytes (IELs) that reside within the epithelium of the intestine form one of the main branches of the immune system. As IELs are located at this critical interface between ...the core of the body and the outside environment, they must balance protective immunity with an ability to safeguard the integrity of the epithelial barrier: failure to do so would compromise homeostasis of the organism. In this Review, we address how the unique development and functions of intestinal IELs allow them to achieve this balance.
“The beginning of wisdom is found in doubting; by doubting we come to question, and by seeking we may come upon the truth.” –Pierre Abélard
CD8 is a glycoprotein expressed on hematopoietic cells. Two ...isoforms of CD8, CD8αβ and CD8αα, have been identified that are distinct in their expression and function. Whereas CD8αβ serves as a T cell receptor (TCR) coreceptor to enhance the functional avidity and is constitutively expressed on MHC class I-restricted T cells, CD8αα marks T cells that are distinct from the conventional thymus-selected and MHC-restricted CD4+ or CD8αβ+ T cells. Inconsistent with a coreceptor function, CD8αα decreases antigen sensitivity of the TCR, and it can be transiently or permanently expressed on T cells, regardless of the MHC restriction of the TCR or the presence of conventional coreceptors. Together, these observations indicate that CD8αα on T cells marks a differentiation stage and that it likely functions as a TCR corepressor to negatively regulate T cell activation.
Objective
Up‐regulation of glucose metabolism has been implicated not only in tumor cell growth but also in immune cells upon activation. However, little is known about the metabolite profile in ...rheumatoid arthritis (RA), particularly in fibroblast‐like synoviocytes (FLS). This study was undertaken to evaluate whether changes in glucose metabolism in RA FLS could play a role in inflammation and joint damage.
Methods
Synovium and FLS were obtained from patients with RA and patients with osteoarthritis (OA). The rate of glycolysis after stimulation of FLS with lipopolysaccharide and platelet‐derived growth factor BB was measured using glycolysis stress test technology. FLS function was evaluated using a glycolysis inhibitor, 2‐deoxy‐d‐glucose (2‐DG). After stimulation of the FLS, a migration scratch assay, MTT assay, and enzyme‐linked immunosorbent assay were performed to measure the effect of 2‐DG on FLS migration, viability of the FLS, and cytokine secretion, respectively. IRDye 800CW 2‐DG was used to assess glucose uptake in the arthritic joints and stromal cells of mice after K/BxN mouse serum transfer. The mice were injected daily, intraperitoneally, with 3‐bromopyruvate (BrPa; 5 mg/kg) to assess the effect of inhibition of glycolysis in vivo.
Results
Compared to human OA FLS, the balance between glycolysis and oxidative phosphorylation was shifted toward glycolysis in RA FLS. Glucose transporter 1 (GLUT1) messenger RNA (mRNA) expression correlated with baseline functions of the RA FLS. Glucose deprivation or incubation of the FLS with glycolytic inhibitors impaired cytokine secretion and decreased the rate of proliferation and migration of the cells. In a mouse model of inflammatory arthritis, GLUT1 mRNA expression in the synovial lining cells was observed, and increased levels of glucose uptake and glycolytic gene expression were detected in the stromal compartment of the arthritic mouse joints. Inhibition of glycolysis by BrPa, administered in vivo, significantly decreased the severity of arthritis in this mouse model.
Conclusion
Targeting metabolic pathways is a novel approach to understanding the mechanisms of disease. Inhibition of glycolysis may directly modulate synoviocyte‐mediated inflammatory functions and could be an effective treatment strategy for arthritis.
Colitis-associated cancer (CAC) is the most serious complication of inflammatory bowel disease. Proinflammatory cytokines have been suggested to regulate preneoplastic growth during CAC ...tumorigenesis. Interleukin 6 (IL-6) is a multifunctional NF-κB-regulated cytokine that acts on epithelial and immune cells. Using genetic tools, we now demonstrate that IL-6 is a critical tumor promoter during early CAC tumorigenesis. In addition to enhancing proliferation of tumor-initiating cells, IL-6 produced by lamina propria myeloid cells protects normal and premalignant intestinal epithelial cells (IECs) from apoptosis. The proliferative and survival effects of IL-6 are largely mediated by the transcription factor Stat3, whose IEC-specific ablation has profound impact on CAC tumorigenesis. Thus, the NF-κB-IL-6-Stat3 cascade is an important regulator of the proliferation and survival of tumor-initiating IECs.
The intestinal intraepithelial lymphocytes (IELs) are mostly T cells dispersed as single cells within the epithelial cell layer that surrounds the intestinal lumen. IELs are, therefore, strategically ...located at the interface between the antigen‐rich outside world and the sterile core of the body. The intestine of higher vertebrates has further evolved to harbor numerous commensal bacteria that carry out important functions for the host, and while defensive immunity can effectively protect against the invasion of pathogens, similar immune reactions against food‐derived antigens or harmless colonizing bacteria can result in unnecessary and sometimes damaging immune responses. Probably as a result of this unique dilemma imposed by the gut environment, multiple subsets of IEL have differentiated, which all display characteristics of ‘activated yet resting’ immune cells. Despite this common feature, IELs are heterogeneous with regard to their phenotype, ontogeny, and function. In this review, we discuss the different subtypes of IELs and highlight the distinct pathways they took that led to their unique differentiation into highly specialized effector memory T cells, which provide the most effective immune protection yet in a strictly regulated fashion to preserve the integrity and vital functions of the intestinal mucosal epithelium.
Innate lymphoid cells (ILCs) are important regulators of early infection at mucosal barriers. ILCs are divided into three groups based on expression profiles, and are activated by cytokines and ...neuropeptides. Yet, it remains unknown if ILCs integrate other signals in providing protection. We show that signaling through herpes virus entry mediator (HVEM), a member of the tumor necrosis factor (TNF) receptor superfamily, in ILC3 is important for host defense against oral infection with the bacterial pathogen Yersinia enterocolitica. HVEM stimulates protective interferon-γ (IFN-γ) secretion from ILCs, and mice with HVEM-deficient ILC3 exhibit reduced IFN-γ production, higher bacterial burdens and increased mortality. In addition, IFN-γ production is critical as adoptive transfer of wild-type but not IFN-γ-deficient ILC3 can restore protection to mice lacking ILCs. We identify the TNF superfamily member, LIGHT, as the ligand inducing HVEM signals in ILCs. Thus HVEM signaling mediated by LIGHT plays a critical role in regulating ILC3-derived IFN-γ production for protection following infection.
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•ILC3 are required for early host defense during Y. enterocolitica infection•IFN-γ from CCR6− ILC3 is essential for protection of mice from Yersinia•HVEM expression by ILC3 is important for IFN-γ production following infection•LIGHT is the ligand for HVEM signaling in regulating ILC3-derived IFN-γ production
Seo et al. find that IFN-γ-producing ILC3 in the small intestine are required for host protection against Yersinia enterocolitica infection. HVEM signaling in ILC3, mediated by the ligand LIGHT, is critical for regulating IFN-γ production for protection following infection.
HVEM is a TNF (tumor necrosis factor) receptor contributing to a broad range of immune functions involving diverse cell types. It interacts with a TNF ligand, LIGHT, and immunoglobulin (Ig) ...superfamily members BTLA and CD160. Assessing the functional impact of HVEM binding to specific ligands in different settings has been complicated by the multiple interactions of HVEM and HVEM binding partners. To dissect the molecular basis for multiple functions, we determined crystal structures that reveal the distinct HVEM surfaces that engage LIGHT or BTLA/CD160, including the human HVEM-LIGHT-CD160 ternary complex, with HVEM interacting simultaneously with both binding partners. Based on these structures, we generated mouse HVEM mutants that selectively recognized either the TNF or Ig ligands in vitro. Knockin mice expressing these muteins maintain expression of all the proteins in the HVEM network, yet they demonstrate selective functions for LIGHT in the clearance of bacteria in the intestine and for the Ig ligands in the amelioration of liver inflammation.
The immune system preserves and makes use of autoreactive lymphocytes with specialized functions. Here we showed that one of these populations, CD8αα
+TCRαβ
+ intestinal intraepithelial lymphocytes ...(IELs), arose from a unique subset of double-positive thymocytes. This subset of cells was precommitted to preferentially give rise to CD8αα
+TCRαβ
+ IELs, but they required exposure to self-agonist peptides. The agonist-selected TCRαβ
+ thymocytes are CD4 and CD8 double-negative, and their final maturation, including the induction of CD8αα expression, appeared to occur only after thymus export in the IL-15-rich environment of the gut. These developmental steps, including precommitment of immature thymocytes, TCR-mediated agonist selection, and postthymic differentiation promoted by cytokines, define a unique pathway for the generation of CD8αα
+TCRαβ
+ IEL.
The B and T lymphocyte attenuator (BTLA) is an Ig super family member that binds to the herpes virus entry mediator (HVEM), a TNF receptor super family (TNFRSF) member. Engagement of BTLA by HVEM ...triggers inhibitory signals, although recent evidence indicates that BTLA also may act as an activating ligand for HVEM. In this study, we reveal a novel role for the BTLA-HVEM pathway in promoting the survival of activated CD8(+) T cells in the response to an oral microbial infection. Our data show that both BTLA- and HVEM-deficient mice infected with Listeria monocytogenes had significantly reduced numbers of primary effector and memory CD8(+) T cells, despite normal proliferation and expansion compared to controls. In addition, blockade of the BTLA-HVEM interaction early in the response led to significantly reduced numbers of antigen-specific CD8(+) T cells. HVEM expression on the CD8(+) T cells as well as BTLA expression on a cell type other than CD8(+) T lymphocytes, was required. Collectively, our data demonstrate that the function of the BTLA-HVEM pathway is not limited to inhibitory signaling in T lymphocytes, and instead, that BTLA can provide crucial, HVEM-dependent signals that promote survival of antigen activated CD8(+) T cell during bacterial infection.
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