Mucosal associated invariant T cells: don't forget your vitamins.

T lymphocytes express clonal receptors, called T cell receptors (TCRs), which specifically recognize antigens presented in combination with major histocompatibility molecules (MHC). To date, T cell antigens can be broadly categorized into two classes: peptides and lipids. A recent paper published in Nature by Kjer-Nielsen and colleagues reveals that a unique population of T lymphocytes expresses TCRs that recognize a completely new and unexpected class of antigens, vitamin metabolites.

MR1 presents microbial vitamin B metabolites to MAIT cells.

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.

Pterins as sensors of response to the application of Fe3+ -dextran in piglets.

The aim of the presented study was to assess the effect of a single administration of Fe(3+)-dextran on immune cell counts and pterin biomolecule production as novel sensors of the piglets' immune system activation, and to determine concentrations of cortisol, a traditional hormonal biosensor of the stress response. Pterins (neopterin and biopterin) in the piglets' blood serum were analyzed by separation using reversed-phase HPLC. A single dose of Fe(3+)-dextran produced a special stress situation in the piglets' organism which manifested itself by an increased production of neopterin (p < 0.05) and biopterin (p < 0.01) in the experimental piglets. Changes in cortisol concentrations and leukocyte counts were influenced by handling stress and were not specifically correlated to iron dextran application. Iron concentrations in the internal environment of the experimental piglets' group were higher by an order of magnitude compared with the controls, and the highest serum concentrations of iron (p < 0.01) were reached 24 h following Fe(3+)-dextran administration. The data presented offer a new perspective on the evaluation of stress situations in the animal organism and, not least importantly, extends the rather modest current list of references on the role of pterins in livestock animals.

Abnormalities in urinary pterin levels in Rett syndrome.

The pterins, neopterin and biopterin, occur naturally in body fluids including urine. Increased neopterin levels are associated with activation of the cellular immune system and reduced biopterins are essential for biosynthesis of the monoamine neurotransmitters. The present study measured urinary neopterin and biopterin by high-performance liquid chromatography in 40 subjects with Rett syndrome, eight of their healthy sisters and 29 female control volunteers (age range 2-54 years). The results confirm earlier preliminary findings that urinary neopterin levels are raised in a proportion of young girls with Rett syndrome but not in the older women. In contrast urinary biopterin levels are not different from controls in the youngest children but remain low while control values increase with age. These findings may indicate immune activation during the regression phase of Rett syndrome but also raise the possibility that an inherited fault in tetrahydrobiopterin metabolism increases the risk of developing the disorder.

Anti-idiotypic antibodies elicited by pterin recognize active site epitopes in dihydrofolate reductases and dihydropteridine reductase.

Monoclonal antibodies (mAbs) against antipterin immunoglobulin and dihydropteridine reductase (DHPR) and also polyclonal antibodies against human dihydrofolate reductase (DHFR) were obtained. The anti-idiotypic mAbs and anti-DHPR mAbs bind specifically to human DHFR, Escherichia coli DHFR, soybean seedling DHFR, and human DHPR in solid-phase immunoassays. Further, the mAbs bind to the native but not to the denatured forms of DHFRs. The monoclonal antibodies also inhibit the enzymatic activity of human DHFR but not that of human DHPR. Competitive solid-phase immunoassays show stoichiometric inhibition by methotrexate and partial inhibition by NADPH of mAb binding to human DHFR. Cyanogen bromide fragments derived from human DHFR (residues 15-52 and 53-111), containing several active site residues, bind partially to some of the monoclonal antibodies. Accordingly, polyclonal antibodies to peptide 53-111 of human DHFR cross-react to some extent with human DHPR. Data from competitive immunoassays in which the binding of the various mAbs was tested singly and in combination with other mAbs suggest that these antibodies bind to a common region on human DHFR. The results also indicate that the mAbs display some heterogeneity with respect to specific epitopes. These data suggest that despite the absence of significant amino acid sequence homologies among the various DHFRs and DHPR, they have a fundamentally similar topography at the site of binding of the pterin moiety that is recognized by the anti-idiotypic mAbs generated by pterin. In the relatively simple structure of the pterin ring system there are different substituent groups at positions C4 and C6 in methotrexate, 7,8-dihydrofolate, and 7,8-dihydrobiopterin, suggesting that these antibodies are specific for regions on various proteins that interact with the remainder of the pterin moiety. These mAbs and similar mAbs specified by substituent groups on pterin may thus be used as specific probes or inhibitors of various folate-dependent enzymes and transport proteins. They should also provide insights into some of the general features of antibody recognition of protein antigens.