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Antigen-presenting molecules, encoded by the major histocompatibility complex (MHC) and CD1 family, bind peptide- and lipid-based antigens, respectively, for recognition by T cells. Mucosal-associated invariant T (MAIT) cells are an abundant population of innate-like T cells in humans that are activated by an antigen(s) bound to the MHC class I-like molecule MR1. Although the identity of MR1-restricted antigen(s) is unknown, it is present in numerous bacteria and yeast. Here we show that the structure and chemistry within the antigen-binding cleft of MR1 is distinct from the MHC and CD1 families. MR1 is ideally suited to bind ligands originating from vitamin metabolites. The structure of MR1 in complex with 6-formyl pterin, a folic acid (vitamin B9) metabolite, shows the pterin ring sequestered within MR1. Furthermore, we characterize related MR1-restricted vitamin derivatives, originating from the bacterial riboflavin (vitamin B2) biosynthetic pathway, which specifically and potently activate MAIT cells. Accordingly, we show that metabolites of vitamin B represent a class of antigen that are presented by MR1 for MAIT-cell immunosurveillance. As many vitamin biosynthetic pathways are unique to bacteria and yeast, our data suggest that MAIT cells use these metabolites to detect microbial infection. The structure of the major histocompatibility complex (MHC)-class-I-like molecule MR1 in complex with a vitamin B9 derivative is determined; metabolites of vitamin B2 are shown to activate MR1-restricted mucosal-associated invariant T cells, implicating them in microbial immunosurveillance. Immune surveillance role for MAIT cells Although mucosal-associated invariant T (MAIT) cells comprise up to 10% of the human T-cell population, surprisingly little is known about their role in physiology and pathology. This is in large part because the identity of the antigen or antigens recognized by MAIT cells in an MR1-restricted manner is unknown. This study reports the structure of the MHC-like molecule MR1 in complex with the vitamin B9-like protein pterin. Bacterial vitamin B derivatives are shown to activate MAIT cells, suggesting that the elusive antigens for MAIT cells are microbial vitamin metabolites and that the physiological role of these cells is to detect microbial infections.

Metabolic enzymes and metabolites display non-metabolic functions in immune cell signalling that modulate immune attack ability. However, whether and how a tumour’s metabolic remodelling contributes to its immune resistance remain to be clarified. Here we perform a functional screen of metabolic genes that rescue tumour cells from effector T cell cytotoxicity, and identify the embryo- and tumour-specific folate cycle enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2). Mechanistically, MTHFD2 promotes basal and IFN-γ-stimulated PD-L1 expression, which is necessary for tumourigenesis in vivo. Moreover, IFN-γ stimulates MTHFD2 through the AKT–mTORC1 pathway. Meanwhile, MTHFD2 drives the folate cycle to sustain sufficient uridine-related metabolites including UDP-GlcNAc, which promotes the global O-GlcNAcylation of proteins including cMYC, resulting in increased cMYC stability and PD-L1 transcription. Consistently, the O-GlcNAcylation level positively correlates with MTHFD2 and PD-L1 in pancreatic cancer patients. These findings uncover a non-metabolic role for MTHFD2 in cell signalling and cancer biology. Metabolites have been reported not only to support the highly-demanding energetic needs of cancer cells but also as signalling regulators. Here, the authors show that the activity of the folate cycle enzyme MTHFD2 stimulates PD-L1 expression impairing T cell-mediated cytotoxicity and promoting tumourigenesis.

β-thalassemia major is one of the most common hematologic disorders in the world. It causes severe anemia and patients require regular blood transfusions, which causes different complications such as iron overload and alloimmunization. Regulatory T cells (Tregs) have an important role in regulation of immune responses. FoxP3 is the major marker of Tregs and its expression can be influenced by different factors. GDF-15 is another gene that plays a role in iron homeostasis and regulation of immune system in different diseases. The aim of this study was to assess the frequency of Tregs and FoxP3/GDF-15 gene expression in β-thalassemia major patients with and without alloantibody as well as its correlation with different factors such as serum ferritin and folate levels. This study was conducted on 68 β-thalassemia major patients with and without alloantibodies in comparison with 20 healthy individuals with matched age and sex as control group. Enzyme-linked immunosorbent assay (ELISA), flow cytometry, and real-time PCR were performed in order to evaluate serum ferritin and folate levels, frequency of Tregs, and the expression of FoxP3 and GDF-15 genes, respectively. The percentage and absolute count of Tregs were increased in patients compared with controls (P = 0.0003), but there was no difference between responders and non-responders (P > 0.05). The Tregs count correlated positively with serum ferritin. No correlation was observed between target genes and serum ferritin and folate, but there was a positive significant correlation between the expression of FoxP3 and GDF-15 genes, which shows the immunosuppressive role of GDF-15.

The mechanism by which periconceptional folate supplementation reduces the incidence of neural-tube defects in the fetuses of women without clinical folate deficiency is unknown. After developing an assay for autoantibodies against the folate receptor, the authors found these autoantibodies in 9 of 12 women with a current or previous pregnancy complicated by a neural-tube defect, as compared with 2 of 20 women with an uncomplicated pregnancy. The autoantibodies blocked the binding of [ 3 H]folic acid to folate receptors in vitro. Autoantibodies against the folate receptor. Neural-tube defects, which include spina bifida, anencephaly, craniorachischisis, and encephalocele, occur in approximately 1 per 1000 births in the United States, and women who have one fetus with this complication are at increased risk in subsequent pregnancies. 1 Although periconceptional folic acid supplementation reduces the occurrence and recurrence of neural-tube defects by approximately 70 percent, 2 , 3 most women who are pregnant with a fetus with this complication do not have clinical folate deficiency. 4 Though some polymorphisms for folate-pathway enzymes have been identified, 5 they cannot account for the 70 percent decrease in the incidence of this birth defect with folate supplementation. Studies . . .

For more than 50 years after Donath and Landsteiner reported the first autoimmune disease in humans, the field of autoimmunization dwelled in a dark age in which the incontrovertibility of horror autotoxicus squelched any proposition that autoantibodies might cause a disease. All that is over, writes Dr. Robert Schwartz, and the study of autoimmunization has entered its golden age. In 1904, a little more than a century ago, Julius Donath, a senior physician working in the Vienna Merchants' Hospital, and Karl Landsteiner, the chair of the pathology department at the University of Vienna and one of the founders of immunochemistry, reported the first known autoimmune disease in humans, paroxysmal cold hemoglobinuria. They showed that an antibody in this disease reacted in the cold with the patient's own erythrocytes. By definition, the Donath–Landsteiner antibody was an autoantibody. This revolutionary discovery flew in the face of “horror autotoxicus,” a principle that Paul Ehrlich had expounded after failing to find autoantibodies in . . .

Childhood cerebral folate deficiency is a disabling neurologic disorder in which folate is reduced in the cerebrospinal fluid but not in the blood. The usual signs of folate deficiency are therefore absent. This study showed that children with cerebral folate deficiency produce autoantibodies that block the binding of folate to the folate receptor. Very high doses of folate resulted in clinical improvement in some children. Children with cerebral folate deficiency produce autoantibodies that block the binding of folate to the folate receptor. This report widens the scope of knowledge about receptor-binding autoantibodies and introduces provocative ideas about certain brain disorders of childhood. Cerebral folate deficiency can be defined as any neuropsychiatric condition associated with low levels of 5-methyltetrahydrofolate (5MTHF), the active folate metabolite in the cerebrospinal fluid, in association with normal folate metabolism outside the central nervous system, as reflected by normal hematologic values, normal serum homocysteine levels, and normal levels of folate in serum and erythrocytes. Infantile-onset cerebral folate deficiency is a neurologic syndrome that develops four to six months after birth. Its major manifestations are marked irritability, slow head growth, psychomotor retardation, cerebellar ataxia, pyramidal tract signs in the legs, dyskinesias (e.g., choreoathetosis and ballismus), and in some cases, seizures. . . .

A micro-analytical system for rapid and quantitative analysis by inhibition immunoassay is presented and applied to the detection of folic acid. Eight polymer microchannels of 65-nL volume each and containing microelectrodes are embedded in a cartridge so that they can be operated simultaneously. All fluidic steps as well as the amperometric detection in the channels are operated by an instrument and software developed in-house. The fluidic steps of the immunoassay occur through hydrodynamic loading of the different solutions through the channels. The speed and duration of the flow and incubation parameters can thus be adapted to the biological and testing requirements. The effectiveness of the system was demonstrated by analysing folic acid concentrations in real infant formula samples within 5 min. In an effort to get a fully monitored assay, each fluidic step is monitored thanks to continuous amperometric detection of oxygen in the microchannel. [graphic removed]

Recent studies revealed that folic acid deficiency (FD) increased the likelihood of stroke and aggravated brain injury after focal cerebral ischaemia. The microglia‐mediated inflammatory response plays a crucial role in the complicated pathologies that lead to ischaemic brain injury. However, whether FD is involved in the activation of microglia and the neuroinflammation after experimental stroke and the underlying mechanism is still unclear. The aim of the present study was to assess whether FD modulates the Notch1/nuclear factor kappa B (NF‐κB) pathway and enhances microglial immune response in a rat middle cerebral artery occlusion‐reperfusion (MCAO) model and oxygen‐glucose deprivation (OGD)‐treated BV‐2 cells. Our results exhibited that FD worsened neuronal cell death and exaggerated microglia activation in the hippocampal CA1, CA3 and Dentate gyrus (DG) subregions after cerebral ischaemia/reperfusion. The hippocampal CA1 region was more sensitive to ischaemic injury and FD treatment. The protein expressions of proinflammatory cytokines such as tumour necrosis factor‐α, interleukin‐1β and interleukin‐6 were also augmented by FD treatment in microglial cells of the post‐ischaemic hippocampus and in vitro OGD‐stressed microglia model. Moreover, FD not only dramatically enhanced the protein expression levels of Notch1 and NF‐κB p65 but also promoted the phosphorylation of pIkBα and the nuclear translocation of NF‐κB p65. Blocking of Notch1 with N‐[N‐(3, 5‐difluorophenacetyl)‐l‐alanyl]‐S‐phenylglycine t‐butyl ester partly attenuated the nuclear translocation of NF‐κB p65 and the protein expression of neuroinflammatory cytokines in FD‐treated hypoxic BV‐2 microglia. These results suggested that Notch1/NF‐κB p65 pathway‐mediated microglial immune response may be a molecular mechanism underlying cerebral ischaemia‐reperfusion injury worsened by FD treatment.

In 1991, a randomized trial funded by the Medical Research Council demonstrated that folic acid supplementation before pregnancy and during its early stages markedly reduced the risk of neural-tube defects in newborns. 1 This finding — which indicated that neural-tube defects may be considered to represent a vitamin-deficiency disorder — led to the recommendation that all women who are planning to become pregnant should take folic acid supplements beginning before pregnancy is recognized and continuing through its early stages. Once a pregnancy has been confirmed, it is probably too late for supplemental folic acid to be protective. In this issue of . . .

Folate supplementation may be associated with an increased risk of developing several types of cancer and a derangement of immune function. Among the latter, Natural killer (NK) cells are involved in non–MHC-restricted natural immunity against malignant target cells. Abnormalities in NK cell number or function have been associated with a higher cancer risk. The aim of this study was to study in vitro the possible effect of different concentrations of 5-methyltetrahydrofolic acid (5-MTHF) or folic acid on NK cell cytotoxic function, and expression of the stimulatory and inhibitory receptors KIRDL4, KIRDL3, and NKG2D. Volunteer-derived peripheral mononuclear cells (PBMC) and highly enriched NK cells (95% CD56+ CD16+) were grown in folic acid free–RPMI 1640, supplemented either with folic acid or 5-MTHF (15–100 nM) during 72 h to 96 h. No differences in the cytolytic activity of PBMC and enriched NK cells were observed. After 96 h of in vitro culture without folate or supplemented with FA or 5-MTHF (30 or 100 nM), there were no changes in the percentage of HPNK receptor-positive cells. Our data indicate that a high dose of 5-MTHF or folic acid does not influence NK cell function in vitro.