Butyrophilin 3A1 binds phosphorylated antigens and stimulates human γδ T cells.
TL;DR: It is found that the butyrophilin BTN3A1 bound phosphorylated antigens with low affinity, at a stoichiometry of 1:1, and stimulated mouse T cells with transgenic expression of a human Vγ9Vδ2 TCR, which represents an antigen-presenting molecule required for the activation of V δ-chain variable region 2 T cells.
Abstract: Vγ9Vδ2-expressing cells are a prominent γδ T cell population, but little is known about how they recognize antigens. De Libero and colleagues identify CD277 as an actual antigen-presenting molecule that binds stimulatory phosphorylated antigens.
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TL;DR: Evidence showing that unconventional T cells are an abundant component of the human immune system is reviewed and the immunotherapeutic potential of these cells and their antigenic targets are discussed.
Abstract: While most studies of T lymphocytes have focused on T cells reactive to complexes of peptide and major histocompatibility complex (MHC) proteins, many other types of T cells do not fit this paradigm. These include CD1-restricted T cells, MR1-restricted mucosal associated invariant T cells (MAIT cells), MHC class Ib-reactive T cells, and γδ T cells. Collectively, these T cells are considered 'unconventional', in part because they can recognize lipids, small-molecule metabolites and specially modified peptides. Unlike MHC-reactive T cells, these apparently disparate T cell types generally show simplified patterns of T cell antigen receptor (TCR) expression, rapid effector responses and 'public' antigen specificities. Here we review evidence showing that unconventional T cells are an abundant component of the human immune system and discuss the immunotherapeutic potential of these cells and their antigenic targets.
599 citations
TL;DR: Functional and molecular analyses indicate that in infections, γδ T cells respond earlier than αβ T cells do and that they emerge late after pathogen numbers start to decline, suggesting that these cells may be involved in both establishing and regulating the inflammatory response.
Abstract: γδ T cells, αβ T cells, and B cells are present together in all but the most primitive vertebrates, suggesting that each population contributes to host immune competence uniquely and that all three are necessary for maintaining immune competence. Functional and molecular analyses indicate that in infections, γδ T cells respond earlier than αβ T cells do and that they emerge late after pathogen numbers start to decline. Thus, these cells may be involved in both establishing and regulating the inflammatory response. Moreover, γδ T cells and αβ T cells are clearly distinct in their antigen recognition and activation requirements as well as in the development of their antigen-specific repertoire and effector function. These aspects allow γδ T cells to occupy unique temporal and functional niches in host immune defense. We review these and other advances in γδ T cell biology in the context of their being the major initial IL-17 producers in acute infection.
477 citations
TL;DR: The current knowledge from both human and mouse studies are integrated to highlight the potential of γδ T cell modulation to improve cancer immunotherapy.
Abstract: With the promise of T cell-based therapy for cancer finally becoming reality, this Review focuses on the less-studied γδ T cell lineage and its diverse responses to tumours. γδ T cells have well-established protective roles in cancer, largely on the basis of their potent cytotoxicity and interferon-γ production. Besides this, recent studies have revealed a series of tumour-promoting functions that are linked to interleukin-17-producing γδ T cells. Here, we integrate the current knowledge from both human and mouse studies to highlight the potential of γδ T cell modulation to improve cancer immunotherapy.
427 citations
TL;DR: A systematic quantitative analysis of temporal changes in host and viral proteins throughout the course of a productive infection could provide dynamic insights into virus-host interaction, applicable to any virus with a robust in vitro model.
378 citations
Cites background from "Butyrophilin 3A1 binds phosphorylat..."
...The T cell costimulators ICOSLG (inducible T cell costimulator ligand) and PD-L2 were downregulated during infection, as was butyrophilin subfamily 3 member A1 (BTN3A1), recently shown to present phosphoantigens to Vg9Vd2+ T cells (Vavassori et al., 2013)....
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TL;DR: The results show that murine epithelial cell-specific Btnl proteins can form intrafamily heterocomplexes and suggest that the interaction between BtNL proteins and IELs regulates the expansion of Iels in the intestinal mucosa.
Abstract: To date, few molecular conduits mediating the cross-talk between intestinal epithelial cells and intraepithelial lymphocytes (IELs) have been described. We recently showed that Butyrophilin-like (Btnl) 1 can attenuate the epithelial response to activated IELs, resulting in reduced production of pro-inflammatory mediators such as IL-6 and CXCL1. We here report that like Btnl1, murine Btnl6 expression is primarily confined to the intestinal epithelium. Although Btnl1 can exist in a cell surface-expressed homomeric form, we found that it additionally forms heteromeric complexes with Btnl6, and that the engagement of Btnl1 is a prerequisite for surface expression of Btnl6 on intestinal epithelial cells. In an IEL-epithelial cell co-culture system, enforced epithelial cell expression of Btnl1 significantly enhanced the proliferation of IELs in the absence of exogenous activation. The effect on proliferation was dependent on the presence of IL-2 or IL-15 and restricted to IELs upregulating CD25. In the gamma delta (gd) T-cell subset, the Btnl1-Btnl6 complex, but not Btnl1, specifically elevated the proliferation of IELs bearing the Vg7Vd4 receptor. Thus, our results show that murine epithelial cell-specific Btnl proteins can form intrafamily heterocomplexes, and suggest that the interaction between Btnl proteins and IELs regulates the expansion of IELs in the intestinal mucosa.
377 citations
Cites background from "Butyrophilin 3A1 binds phosphorylat..."
...Furthermore, it was recently reported that human BTN3A1 can present phosphoantigens to human Vγ9Vδ2 T cells, and hence can act as an antigen-presenting molecule regulating the function of unconventional T cells (16, 17)....
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TL;DR: In this article, surface-enhanced Raman scattering was used to detect single molecules and single nanoparticles at room temperature with the use of surface enhanced Raman, and the intrinsic Raman enhancement factors were on the order of 10 14 to 10 15, much larger than the ensemble-averaged values derived from conventional measurements.
Abstract: Optical detection and spectroscopy of single molecules and single nanoparticles have been achieved at room temperature with the use of surface-enhanced Raman scattering. Individual silver colloidal nanoparticles were screened from a large heterogeneous population for special size-dependent properties and were then used to amplify the spectroscopic signatures of adsorbed molecules. For single rhodamine 6G molecules adsorbed on the selected nanoparticles, the intrinsic Raman enhancement factors were on the order of 10 14 to 10 15 , much larger than the ensemble-averaged values derived from conventional measurements. This enormous enhancement leads to vibrational Raman signals that are more intense and more stable than single-molecule fluorescence.
9,609 citations
TL;DR: It is shown that formation of peptide–MHC class II complexes is boosted by inflammatory stimuli that induce maturation of dendritic cells, which could favour presentation of infectious antigens.
Abstract: Dendritic cells have the remarkable property of presenting any incoming antigen. To do so they must not only capture antigens with high efficiency and broad specificity, but must also maximize their capacity to load class II molecules of the major histocompatibility complex (MHC) with antigenic peptides in order to present a large array of epitopes from different proteins, each at a sufficient copy number. Here we show that formation of peptide-MHC class II complexes is boosted by inflammatory stimuli that induce maturation of dendritic cells. In immature dendritic cells, class II molecules are rapidly internalized and recycled, turning over with a half-life of about 10 hours. Inflammatory stimuli induce a rapid and transient boost of class II synthesis, while the half-life of class II molecules increases to over 100 hours. These coordinated changes result in the rapid accumulation of a large number of long-lived peptide-loaded MHC class II molecules capable of stimulating T cells even after several days. The capacity of dendritic cells to load many antigenic peptides over a short period of initial exposure to inflammatory stimuli could favour presentation of infectious antigens.
1,152 citations
TL;DR: The properties of g Mohammadelta cells form a basis for understanding gammadelta cell interactions with antigens and other cells that in turn form a based for understanding immunoprotective and regulatory functions of gammad delta cells in vivo.
Abstract: The tripartite subdivision of lymphocytes into B cells, αβ T cells, and γδ cells has been conserved seemingly since the emergence of jawed vertebrates, more than 450 million years ago. Yet, while we understand much about B cells and αβ T cells, we lack a compelling explanation for the evolutionary conservation of γδ cells. Such an explanation may soon be forthcoming as advances in unraveling the biochemistry of γδ cell interactions are reconciled with the abnormal phenotypes of γδ-deficient mice and with the striking differences in γδ cell activities in different strains and species. In this review, the properties of γδ cells form a basis for understanding γδ cell interactions with antigens and other cells that in turn form a basis for understanding immunoprotective and regulatory functions of γδ cells in vivo. We conclude by considering which γδ cell functions may be most critical.
1,132 citations
TL;DR: It is shown that metabolites of vitamin B represent a class of antigen that are presented by MR1 for MAIT-cell immunosurveillance, and data suggest that MAIT cells use these metabolites to detect microbial infection.
Abstract: 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.
1,082 citations
TL;DR: Results provide formal evidence that, in contrast to recognition of major histocompatibility complex-bound peptide antigens by αβ T cells, human γδ T cells can recognize naturally occurring small non-peptidic antIGens.
Abstract: T lymphocytes express either alpha beta or gamma delta T-cell receptor heterodimers. Most alpha beta T cells recognize antigenic peptides bound to major histocompatibility complex molecules but the antigen recognition and biological function of gamma delta T cells is unknown. A major human gamma delta T-cell subset expressing V gamma 2 and V delta 2 germline genes, but having diverse junctional sequences, is found in human mycobacterial lesions and responds in vitro to antigens of bacteria and parasites. In addition, certain haematopoietic tumour cells are specifically recognized and lysed by these T cells. V gamma 2V delta 2-bearing T cells were shown to recognize mycobacterial antigens that are protease resistant and phosphatase sensitive. Because of the difficulty in isolating natural antigens from mycobacterial culture filtrates or extracts, we synthesized a series of monoalkyl phosphates, and found that some, particularly monoethyl phosphate, could mimic the activity of mycobacterial antigens in stimulating these gamma delta T cells. Here we report the identification of natural antigens produced by mycobacteria recognized by human V gamma 2V delta 2-bearing T cells as isopentenyl pyrophosphate and related prenyl pyrophosphate derivatives, compounds involved in the synthesis of complex polyisoprenoid compounds in microbial and mammalian cells. Substitution of phosphate for the pyrophosphate moiety, or elimination of the double bond, greatly reduced antigenic activity of these compounds. These results provide formal evidence that, in contrast to recognition of major histocompatibility complex-bound peptide antigens by alpha beta T cells, human gamma delta T cells can recognize naturally occurring small non-peptidic antigens.
956 citations