A new element within the T-cell receptor alpha locus required for tissue-specific locus control region activity.
(1/1935)
Locus control regions (LCRs) are cis-acting regulatory elements thought to provide a tissue-specific open chromatin domain for genes to which they are linked. The gene for T-cell receptor alpha chain (TCRalpha) is exclusively expressed in T cells, and the chromatin at its locus displays differentially open configurations in expressing and nonexpressing tissues. Mouse TCRalpha exists in a complex locus containing three differentially regulated genes. We previously described an LCR in this locus that confers T-lineage-specific expression upon linked transgenes. The 3' portion of this LCR contains an unrestricted chromatin opening activity while the 5' portion contains elements restricting this activity to T cells. This tissue-specificity region contains four known DNase I hypersensitive sites, two located near transcriptional silencers, one at the TCRalpha enhancer, and another located 3' of the enhancer in a 1-kb region of unknown function. Analysis of this region using transgenic mice reveals that the silencer regions contribute negligibly to LCR activity. While the enhancer is required for complete LCR function, its removal has surprisingly little effect on chromatin structure or expression outside the thymus. Rather, the region 3' of the enhancer appears responsible for the tissue-differential chromatin configurations observed at the TCRalpha locus. This region, herein termed the "HS1' element," also increases lymphoid transgene expression while suppressing ectopic transgene activity. Thus, this previously undescribed element is an integral part of the TCRalphaLCR, which influences tissue-specific chromatin structure and gene expression. (+info)
Crystal structure of an MHC class I presented glycopeptide that generates carbohydrate-specific CTL.
(2/1935)
T cell receptor (TCR) recognition of nonpeptidic and modified peptide antigens has been recently uncovered but is still poorly understood. Immunization with an H-2Kb-restricted glycopeptide RGY8-6H-Gal2 generates a population of cytotoxic T cells that express both alpha/beta TCR, specific for glycopeptide, and gamma/delta TCR, specific for the disaccharide, even on glycolipids. The crystal structure of Kb/RGY8-6H-Gal2 now demonstrates that the peptide and H-2Kb structures are unaffected by the peptide glycosylation, but the central region of the putative TCR binding site is dominated by the extensive exposure of the tethered carbohydrate. These features of the Kb/RGY8-6H-Gal2 structure are consistent with the individual ligand binding preferences identified for the alpha/beta and gamma/delta TCRs and thus explain the generation of a carbohydrate-specific T cell response. (+info)
gammadelta T cells contribute to control of chronic parasitemia in Plasmodium chabaudi infections in mice.
(3/1935)
During a primary infection of mice with Plasmodium chabaudi, gammadelta T cells are stimulated and their expansion coincides with recovery from the acute phase of infection in normal mice or with chronic infections in B cell-deficient mice (mu-MT). To determine whether the large gammadelta T cell pool observed in female B cell-deficient mice is responsible for controlling the chronic infection, studies were done using double-knockout mice deficient in both B and gammadelta cells (mu-MT x delta-/-TCR) and in gammadelta T cell-depleted mu-MT mice. In both types of gammadelta T cell-deficient mice, the early parasitemia following the peak of infection was exacerbated, and the chronic parasitemia was maintained at significantly higher levels in the absence of gammadelta T cells. The majority of gammadelta T cells in C57BL/6 and mu-MT mice responding to infection belonged predominantly to a single family of gammadelta T cells with TCR composed of Vgamma2Vdelta4 chains and which produced IFN-gamma rather than IL-4. (+info)
Macrophage control of herpes simplex virus type 1 replication in the peripheral nervous system.
(4/1935)
After corneal infection, herpes simplex virus type 1 (HSV-1) invades sensory neurons with cell bodies in the trigeminal ganglion (TG), replicates briefly, and then establishes a latent infection in these neurons. HSV-1 replication in the TG can be detected as early as 2 days after corneal infection, reaches peak titers by 3-5 days after infection, and is undetectable by 7-10 days. During the period of HSV-1 replication, macrophages and gammadelta TCR+ T lymphocytes infiltrate the TG, and TNF-alpha, IFN-gamma, the inducible nitric oxide synthase (iNOS) enzyme, and IL-12 are expressed. TNF-alpha, IFN-gamma, and the iNOS product nitric oxide (NO) all inhibit HSV-1 replication in vitro. Macrophage and gammadelta TCR+ T cell depletion studies demonstrated that macrophages are the main source of TNF-alpha and iNOS, whereas gammadelta TCR+ T cells produce IFN-gamma. Macrophage depletion, aminoguanidine inhibition of iNOS, and neutralization of TNF-alpha or IFN-gamma all individually and synergistically increased HSV-1 titers in the TG after HSV-1 corneal infection. Moreover, individually depleting macrophages or neutralizing TNF-alpha or IFN-gamma markedly reduced the accumulation of both macrophages and gammadelta TCR+ T cells in the TG. Our findings establish that after primary HSV-1 infection, the bulk of virus replication in the sensory ganglia is controlled by macrophages and gammadelta TCR+ T lymphocytes through their production of antiviral molecules TNF-alpha, NO, and IFN-gamma. Our findings also strongly suggest that cross-regulation between these two cell types is necessary for their accumulation and function in the infected TG. (+info)
T-cell development: What does Notch do for T cells?
(5/1935)
During their development, T cells are rescued from apoptotic cell death to follow distinct lineage fates. Recent data concerned with the role of the Notch transmembrane receptor in these events are interpreted to show that Notch promotes survival, but contrary to earlier reports has no function in lineage commitment. (+info)
IL-12-mediated NKRP1A up-regulation and consequent enhancement of endothelial transmigration of V delta 2+ TCR gamma delta+ T lymphocytes from healthy donors and multiple sclerosis patients.
(6/1935)
Gamma delta T lymphocytes are thought to play a role in the pathogenesis of multiple sclerosis (MS) contributing to demyelinization and fibrosis in the central nervous system. In this study, we show that, in MS patients with active disease, the percentage of circulating V delta 2+ gamma delta T cells coexpressing NKRP1A is significantly increased compared with healthy donors. V delta 2+ and V delta 1+ T cells were sorted from MS patients and healthy volunteers and cloned. At variance with V delta 1+ clones, all V delta 2+ clones expressed NKRP1A, which was strongly up-regulated upon culture with IL-12; this effect was neutralized by specific anti-IL-12 Abs. No up-regulation of NKRP1A by IL-12 was noted on V delta 1+ clones. RNase protection assay showed that IL-12R beta 2 subunit transcript was significantly less represented in V delta 1+ than V delta 2+ clones. This finding may explain the different effect exerted by IL-12 on these clones. In transendothelial migration assays, V delta 2+ NKRP1A+ clones migrated more effectively than V delta 1+ clones, and this migratory potential was enhanced following culture with IL-12. Migration was strongly inhibited by the F(ab')2 of an anti-NKRP1A Ab, suggesting that this lectin is involved in the migration process. We also show that, in freshly isolated PBMC from MS patients, the migrated population was enriched for V delta 2+ NKRP1A+ cells. We conclude that the expression of NKRP1A on V delta 2+ cells is associated with increased ability to migrate across the vascular endothelium and that this phenomenon may be regulated by IL-12 present in the microenvironment. (+info)
Inflammation alone evokes the response of a TCR-invariant mouse gamma delta T cell subset.
(7/1935)
Whether gamma delta T lymphocytes respond to microbial Ags or to inducible host Ags remains a matter of controversy. Using several different disease models and mouse strains, we and others have seen that V gamma 6/V delta 1 gamma delta T cells preferentially increase among the gamma delta T cells infiltrating inflamed tissues. However, it was not clear whether bacteria are necessary to bring about this response. Therefore, we have reexamined this question using a disease model in which inflammation is induced by a purely autoimmune process involving no bacteria, bacterial products, or other foreign material: testicular cell-induced autoimmune orchitis. Using this model we found that gamma delta T cells were still plentiful among the infiltrating T lymphocytes, being 9- to 10-fold more prevalent than in spleen, and that V gamma 6/V delta 1+ cells again represented the predominant gamma delta T cell type. This finding shows that the response of the V gamma 6/V delta 1+ subset does not, in fact, depend upon the presence of bacteria or bacterial products. The stimulus triggering the response of the V gamma 6/V delta 1 gamma delta T cells appears to be neither foreign nor organ-specific in origin, but instead consists of a self-derived host Ag or signal induced during the inflammatory process. (+info)
A circulating bovine gamma delta T cell subset, which is found in large numbers in the spleen, accumulates inefficiently in an artificial site of inflammation: correlation with lack of expression of E-selectin ligands and L-selectin.
(8/1935)
Tissue-specific localization of TCR-defined subsets of gamma delta T cells has been widely reported; however, the mechanisms responsible for this phenomenon are poorly understood. We describe a bovine gamma delta T cell TCR-associated subset that preferentially localizes in the spleen. This subset was characterized by coexpression of CD8, and was found to lack surface expression of E-selectin ligands, GR Ag ligands, as well as low expression of L-selectin. The CD8-positive gamma delta T cell subset did not accumulate at sites of inflammation as efficiently as CD8-negative gamma delta T cells that, in contrast, express E-selectin and GR ligands and high levels of L-selectin. This is the first demonstration of a gamma delta T cell subset, which exhibits a defined tissue tropism, having a unique adhesion molecule expression profile. These results demonstrate that in some cases tissue-specific accumulation of gamma delta T cell subsets can be predicted by expression, or lack of expression, of defined homing molecules. (+info)