Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038362 (stomatitis)
 8,852 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The x-ray structures of a murine MHC class I molecule (H-2Kb) were determined in complex with two different viral peptides, derived from the vesicular stomatitis virus nucleoprotein (52-59), VSV-8, and the Sendai virus nucleoprotein (324-332), SEV-9. The H-2Kb complexes were refined at 2.3 A for VSV-8 and 2.5 A for SEV-9. The structure of H-2Kb exhibits a high degree of similarity with human HLA class I, although the individual domains can have slightly altered dispositions. Both peptides bind in extended conformations with most of their surfaces buried in the H-2Kb binding groove. The nonamer peptide maintains the same amino- and carboxyl-terminal interactions as the octamer primarily by the insertion of a bulge in the center of an otherwise beta conformation. Most of the specific interactions are between side-chain atoms of H-2Kb and main-chain atoms of peptide. This binding scheme accounts in large part for the enormous diversity of peptide sequences that bind with high affinity to class I molecules. Small but significant conformational changes in H-2Kb are associated with peptide binding, and these synergistic movements may be an integral part of the T cell receptor recognition process.
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PMID:Crystal structures of two viral peptides in complex with murine MHC class I H-2Kb. 150 54

During most immune responses, T cells help antigen-specific B cells to make antibodies against the antigen. One of the contributions of T cells to antibody production is the induction of isotype switching from IgM to IgG, which is the most abundant isotype in blood serum during recall responses. Other features of memory responses are faster kinetics and higher titers of antibody in the serum. What causes a primary immune response to be different from a secondary is not yet very clear and, particularly, the influence of precursor frequencies of T and B cells on memory responses still remains to be answered. To address this issue, a transgenic (tg) mouse line (ADA) was developed; it expresses the beta chain (V beta 2) of a major histocompatibility complex class II-restricted T cell receptor (TcR) specific for the glycoprotein (G) of vesicular stomatitis virus (VSV) serotype Indiana (VSV-IND). These mice exhibit an increased precursor frequency of VSV-specific CD4+ T cells that leads to enhanced neutralizing IgG production against VSV in vivo in unprimed mice. The data indicate that increased frequency of naive specific helper T cells alone may account for features of a memory phenotype such as high titer of antibodies and isotype switching.
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PMID:Role of T helper cell precursor frequency on vesicular stomatitis virus neutralizing antibody responses in a T cell receptor beta chain transgenic mouse. 753 59

Carbohydrate antigens rarely provide target epitopes for cytotoxic T lymphocytes (CTL). Disialoganglioside GD2 is a glycolipid expressed at high levels in human tumors and a small group of murine lymphomas (EL4, RBL5, RMA, RMA-S, A13, and BALBRVE). Immunization of C57B1/6 mice with irradiated EL4 cells stimulated a specific CTL response and protected these animals from engraftment of EL4 lymphoma. The CTL activity resided in the CD4-CD8+ population, was dependent on T cell receptor alpha/beta, and was not removed by anti-natural killer cell immunoabsorption, but was restricted to GD2 and H-2b bearing targets. CTL activity could be completely inhibited by GD2-oligosaccharide-specific monoclonal antibodies and their F(ab')2 fragments, but not by immunoglobulin G3 myelomas or antibodies against GD3 or GM2. Soluble GD2 did not inhibit specific tumor lysis. RMA-S lymphoma cells (GD2+H-2b-TAP2 deficient) were resistant to GD2-specific CTL. Sialic acid-containing peptides eluted from EL4 lymphoma cells could (a) stabilize H-2 molecules on RMA-S cells and (b) sensitize them for GD2-specific CTL. Control peptides (derived from vesicular stomatitis virus nucleoprotein peptide and GD2-negative lymphomas) could also stabilize H-2 on RMA-S, but were resistant to GD2-specific CTL. These H-2-binding peptides could be purified by anti-GD2 affinity chromatography. We postulate a new class of naturally occurring epitopes for T cells where branched-chain oligosaccharides are linked to peptides with anchoring motifs for the major histocompatibility complex class I pocket. While analogous to the haptens trinitrophenyl and O-beta-linked acetyl-glucosamine, the potential implications of natural carbohydrates as antigenic epitopes for CTL in biology are considerable.
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PMID:GD2 oligosaccharide: target for cytotoxic T lymphocytes. 754 Jun 57

We examined T cell development and T cell repertoire in transgenic mice expressing a single T cell receptor (TCR) alpha chain derived from the H-2Db-lymphocytic choriomeningitis virus (LCMV)-specific cytolytic T lymphocyte (CTL) clone P14. To generate these alpha P14 mice, mice transgenic for the P14 TCR alpha chain were backcrossed to TCR alpha-deficient mice. Thymi from alpha P14 mice exhibited a marked decrease of mature CD4+8- and CD8+4- single-positive thymocytes comparable to thymi from TCR alpha-deficient mice. Correspondingly, the number of peripheral T cells was reduced in the CD4 (tenfold) and in the CD8 (twofold) subsets when compared to normal mice. T cells from alpha P14 mice generated a primary anti-LCMV CTL response when stimulated in vitro with LCMV in contrast to normal mice which require priming in vivo; elimination of LCMV in vivo was, however, not improved. Flow cytometric analysis of T cells with V beta-specific antibodies showed a diverse endogenous TCR V beta repertoire. Functional analysis of the T cell repertoire, however, revealed a strongly reduced (30-fold) allogeneic and the absence of a vesicular stomatitis virus-specific CTL response and an impaired ability to provide T cell help for antibody isotype switching. Thus, T cell selection in the thymus was impaired and the T cell repertoire was limited in mice expressing only one type of TCR alpha chain.
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PMID:T cell development and repertoire of mice expressing a single T cell receptor alpha chain. 758 40

T cell receptor stimulation without costimulation is insufficient for the induction of an optimal immune response. It is thought that engagement of the CD28 molecule with its ligand B7 provides an essential costimulatory signal without which full activation of T cells cannot occur. A mouse strain with a defective CD28 gene was established. Development of T and B cells in the CD28-deficient mice appeared normal. However, T lymphocytes derived from CD28-/- mutant mice had impaired responses to lectins. Lectin stimulation did not trigger interleukin-2 (IL-2) production, IL-2 receptor alpha expression was significantly decreased, and exogenous IL-2 only partially rescued the CD28 defect. Basal immunoglobulin (Ig) concentrations in CD28-deficient mice were about one-fifth of those found in wild-type controls, with low titers of IgG1 and IgG2b but an increase in IgG2a. In addition, activity of T helper cells in CD28-/- mice was reduced and immunoglobulin class switching was diminished after infection with vesicular stomatitis virus. However, cytotoxic T cells could still be induced and the mice showed delayed-type hypersensitivity after infection with lymphocytic choriomeningitis virus. Thus, CD28 is not required for all T cell responses in vivo, suggesting that alternative costimulatory pathways may exist.
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PMID:Differential T cell costimulatory requirements in CD28-deficient mice. 768 39

As an approach to determine the structural basis of interactions between T cell receptors (TCRs) and MHC class I/peptide complexes, the fine specificities of a panel of vesicular stomatitis virus (VSV)-specific CTL clones recognizing the antigenic peptide (nucleoprotein 52-59) and the class I (Kb) molecule were correlated with the TCR primary structure. Each TCR showed a distinct interaction pattern with N52-59 and the Kb molecule. The large majority of the TCRs expressed by the panel of CTL clones used V beta 13 gene segments that had randomly recombined with D beta and J beta gene segments. The alpha chains were from randomly assorted V alpha and J alpha gene segments. Thus, the panel was found to be a highly heterogeneous set of TCRs, each member of which appeared to have an unique surface interface area, the recognition site, that interacted with a complementary surface formed by the single peptide bound in the class I antigenic groove.
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PMID:Diversity of T cell receptors specific for the VSV antigenic peptide (N52-59) bound by the H-2Kb class I molecule. 774 62

Induction of T-helper cells and T-B cell interaction have been considered to critically depend upon recognition of major histocompatibility complex (MHC) class II molecules by the T cell receptor. Mice lacking either MHC class II molecules (class II(0/0) mice) or its associated invariant chain (Ii0/0 mice) provide new opportunities to test this premise. Immune responses to some protein antigens have been studied in these mice; little is known about their ability to withstand viral infections. We therefore tested CD8+ effector T cells and CD4+ T-cell-dependent B cell function during different viral infections. The vesicular stomatitis virus (VSV)-specific primary cytotoxic T cell response which is largely T-helper-dependent was diminished in Ii(0/0) and absent in class II(0/0) mice. The usually less T-helper-dependent cytotoxic vaccinia or lymphocytic choriomeningitis virus (LCMV)-specific CD8+ T cell responses were reduced up to ninefold in class II(0/0) and up to threefold in Ii(0/0) mice. In class II(0/0) mice, the T-helper-independent neutralizing IgM response against the glycoprotein of VSV was within normal ranges but, in contrast to previous results on CD4(0/0) mice, the T-helper-dependent IgG response was absent. Ii(0/0) mice exhibited a normal neutralizing IgM response; in contrast to class II(0/0) mice, they mounted a significant, though reduced specific IgG response. Similar results were obtained for antibody responses against the nucleoprotein of VSV. Although the T-helper-cell response upon infection with VSV seemed diminished only a little in Ii(0/0) mice, presentation of VSV-G to a class II-restricted specific hybridoma was greater than 300-fold reduced in the absence of Ii. This suggests that local protein concentrations reached during viral infection in the host are high enough to override the Ii deficiency of antigen-presenting cells in vivo.
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PMID:Antiviral immune responses of mice lacking MHC class II or its associated invariant chain. 854 34

Cytotoxic T cells (CTL) recognize target proteins as short peptides presented by major histocompatibility complex (MHC) class I restriction elements. However, there is also evidence for peptide-independent T cell receptor (TCR) recognition of target proteins and non-protein structures. How such T cell responses are generated is presently unclear. We generated carbohydrate (CHO)-specific, MHC-unrestricted CTL responses by coupling di- and trisaccharides to Kb- or Db-binding peptides for direct immunization in mice. Four peptides and three CHO have been analyzed with the CHO either in terminal or central position on the carrier peptide. With two of these glycopeptides, with galabiose (Gal alpha 1-4Gal; Gal2) bound to a homocysteine (via an ethylene spacer arm) in position 4 or 6 in a vesicular stomatitis virus nucleoprotein-derived peptide (RGYVYQGL binding to Kb), CTL were generated which preferentially killed target cells treated with glycopeptide compared to those treated with the core peptide. Polyclonal CTL were also found to kill target cells expressing the same Gal2 epitope in a glycolipid. By fractionation of CTL, preliminary data indicate that glycopeptide-specific Kb-restricted CTL and unrestricted CHO-specific CTL belong to different T cell populations with regard to TCR expression. The results demonstrate that hapten-specific unrestricted CTL responses can be generated with MHC class I-binding carrier peptides. Different models that might explain the generation of such responses are discussed.
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PMID:Immunization with glycosylated Kb-binding peptides generates carbohydrate-specific, unrestricted cytotoxic T cells. 860 19

Experimental analyses of the acute cytotoxic T lymphocyte (CTL) response to viruses have focused on studying these infections in immunologically naive hosts. In the natural environment, however, viral CTL responses occur in hosts that are already immune to other infectious agents. To address which factors contribute to the maintenance and waning of immunological memory, the following study examined the frequencies of virus-specific CTL precursor cells (pCTL) not only using the usual experimental paradigm where mice undergo acute infections with a single virus, and in mice immune to a single virus, but also in immune mice after challenge with various heterologous viruses. As determined by limiting dilution assays, the pCTL frequency (p/f) per CD8+ T cell specific for lymphocytic choriomeningitis virus (LCMV), Pichinde virus (PV), or vaccinia virus (VV) increased during the acute infections, peaking at days 7-8 with frequencies as high as 1/27-1/74. Acute viral infections such as these elicit major expansions in the CD8+ T cell number, which has been reported to undergo apoptosis and decline after most of the viral antigen has been cleared. Although the decline in the total number of virus-specific pCTL after their peak in the acute infection was substantial, for all three viruses the virus-specific p/f per CD8+ T cell decreased only two- to fourfold and remained at these high levels with little fluctuation for well over a year. The ratios of the three immunodominant peptide-specific to total LCMV-specific clones remained unchanged between days 7 and 8 of acute infection and long-term memory, suggesting that the apoptotic events did not discriminate on the basis of T cell receptor specificity, but instead nonspecifically eliminated a large proportion of the activated T cells. However, when one to five heterologous viruses (LCMV, PV, VV, murine cytomegalovirus, and vesicular stomatitis virus) were sequentially introduced into this otherwise stable memory pool, the stability of the memory pool was disrupted. With each successive infection, after the immune system had returned to homeostasis, the memory p/f specific to viruses from earlier infections declined. Reductions in memory p/f were observed in all tested immunological compartments (spleen, peripheral blood, lymph nodes, and peritoneal cavity), and on average in the spleen revealed a 3 +/- 0.4-fold decrease in p/f after one additional viral infection and an 8.4 +/- 3-fold decrease after two additional viral infections. Thus, subsequent challenges with heterologous antigens, which themselves induce memory CTL, may contribute to the waning of CTL memory pool to earlier viruses as the immune system accommodates ever-increasing numbers of new memory cells within a limited lymphoid population. This demonstrates that virus infections do not occur in immunological isolation, and that CD8+ T cell responses are continually being modulated by other infectious agents.
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PMID:Reduction of otherwise remarkably stable virus-specific cytotoxic T lymphocyte memory by heterologous viral infections. 867 69

The molecular interactions between the CD8 co-receptor dependent N15 and N26 T cell receptors (TCRs) and their common ligand, the vesicular stomatitis virus octapeptide (VSV8) bound to H-2Kb, were studied to define the docking orientation(s) of MHC class I restricted TCRs during immune recognition. Guided by the molecular surfaces of the crystallographically defined peptide/MHC and modeled TCRs, a series of mutations in exposed residues likely contacting the TCR ligand were analyzed for their ability to alter peptide-triggered IL-2 production in T cell transfectants. Critical residues which diminished antigen recognition by 1000 to 10,000-fold in molar terms were identified in both N15 Valpha (alphaE94A or alphaE94R, Y98A and K99) and Vbeta (betaR96A, betaW97A and betaD99A) CDR3 loops. Mutational analysis indicated that the Rp1 residue of VSV8 is critical for antigen recognition of N15 TCR, but R62 of H-2Kb is less critical. More importantly, the alphaE94R mutant could be fully complemented by a reciprocal charge reversal at Kb R62 (R62E). This result suggests a direct interaction between N15 TCR Valpha E94R and Kb R62E residues. As Rp1 of VSV8 is adjacent to R62 in the VSV8/Kb complex and essential for T cell activation, this orientation implies that the N15 Valpha CDR3 loop interacts with the N-terminal residues of VSV8 with the Valpha domain docking to the Kb alpha2 helix while the N15 Vbeta CDR3 loop interacts with the more C-terminal peptide residues and the Vbeta domain overlies the Kb alpha1 helix. An equivalent orientation is suggested for N26, a second VSV8/Kb specific TCR. Given that genetic analysis of two different class II MHC-restricted TCRs and two crystallographic studies of class I restricted TCRs offers a similar overall orientation of V domains relative to alpha-helices, these data raise the possibility of a common docking mode between TCRs and their ligands regardless of MHC restriction.
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PMID:Topology of T cell receptor-peptide/class I MHC interaction defined by charge reversal complementation and functional analysis. 926 59


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