scholarly journals Allelic Variation of MHC Structure Alters Peptide Ligands to Induce Atypical Partial Agonistic CD8+ T Cell Function

2003 ◽  
Vol 198 (1) ◽  
pp. 99-109 ◽  
Author(s):  
Dong-Gyun Lim ◽  
Jacqueline M. Slavik ◽  
Katarzyna Bourcier ◽  
Kathrine J. Smith ◽  
David A. Hafler
Keyword(s):  
T Cell ◽  
Intracellular Signaling ◽  
Cell Function ◽  
Peptide Ligands ◽  
T Cell Clones ◽  
Altered Peptide Ligands ◽  
Mhc Molecules ◽  
Cell Functions ◽  
T Cell Function ◽  
Cell Clones

T cell receptors recognize small changes in peptide ligands leading to different T cell responses. Here, we analyzed a panel of HLA-A2–Tax11-19 reactive T cell clones to examine how small allelic variations of MHC molecules could alter the functional outcome of antigen recognition. Similar to the effects induced by antigenic altered peptide ligands, weak or partial agonistic T cell functions were identified in individual T cell clones with the recognition of MHC-altered peptide ligands (MAPLs). Interestingly, one subtype of HLA-A2 molecules induced an unusual type of partial agonistic function; proliferation without cytotoxicity. Modeling of crystallographic data indicated that polymorphic amino acids in the HLA-A2 peptide binding groove, especially the D-pocket, were responsible for this partial agonism. Reciprocal mutations of the Tax peptide side chain engaging the D-pocket indeed restored the agonist functions of the MHC–peptide complex. Whereas early intracellular signaling events were not efficiently induced by these MAPLs, phosphorylated c-Jun slowly accumulated with sustained long-term expression. These data indicate that MAPLs can induce atypical partial agonistic T cell function through structural and biochemical mechanisms similar to altered peptide ligands.

HBV variants create “altered peptide ligands” which results in altered CD4+ T-cell function

1998 ◽  
Vol 28 ◽  
pp. 50
Author(s):  
M.-C. Jung ◽  
J.T. Gerlach ◽  
T. Santantonio ◽  
H. Diepolder ◽  
E. Wierenga ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Function ◽  
Peptide Ligands ◽  
Cd4 T Cell ◽  
Altered Peptide Ligands ◽  
T Cell Function ◽  
Hbv Variants

Cross-Reactivity of T-Cell Clones Specific for Altered Peptide Ligands of Myelin Basic Protein

1999 ◽  
Vol 193 (1) ◽  
pp. 99-107 ◽  
Author(s):  
Lara J. Ausubel ◽  
Katarzyna D. Bieganowska ◽  
David A. Hafler
Keyword(s):  
T Cell ◽  
Myelin Basic Protein ◽  
Basic Protein ◽  
Cross Reactivity ◽  
Peptide Ligands ◽  
T Cell Clones ◽  
Altered Peptide Ligands ◽  
Cell Clones

scholarly journals Specificity of T cell clones for antigen and autologous major histocompatibility complex products determines specificity for foreign major histocompatibility complex products.

1983 ◽  
Vol 158 (2) ◽  
pp. 428-437 ◽  
Author(s):  
S R Abromson-Leeman ◽  
H Cantor
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Molecular Mimicry ◽  
Class Ii ◽  
Major Histocompatibility ◽  
T Cell Clones ◽  
Complex Products ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Cell Clones

We have analyzed a panel of T cell clones that corecognize defined epitopes of the insulin molecule in association with Ia for their patterns of recognition of alloantigens. A striking correlation is observed between recognition of the I-Ab gene product and cow insulin alpha loop and recognition of I-Eu of the PL/J haplotype. These results are consistent with the notion that reactions to foreign major histocompatibility complex (MHC) products reflect molecular mimicry by foreign class II antigens of 'physiologic' complexes formed by autologous class II MHC molecules and antigen.

Mapping the H-Y gene

Development ◽  
1987 ◽  
Vol 101 (Supplement) ◽  
pp. 157-161
Author(s):  
Elizabeth Simpson ◽  
Phillip Chandler ◽  
Anne McLaren ◽  
Els Goulmy ◽  
Christine M. Disteche ◽  
...  
Keyword(s):  
T Cell ◽  
Y Chromosome ◽  
Normal Mouse ◽  
Linked Gene ◽  
T Cell Clones ◽  
Mhc Molecules ◽  
Antigen Gene ◽  
Cell Clones ◽  
Gene Maps

This paper uses cytotoxic and proliferative T cell clones specific for H-Y and restricted by MHC molecules to type mice and humans inheriting incomplete portions of the Y chromosome. The data have allowed us to map the H-Y antigen gene Hya in mouse to a position closely linked with, but separable from, Tdy on the Sxr fragment and thus presumably to a position of the normal mouse Y chromosome near the centromere. The human H-Y gene maps between deletion intervals 4B and 7, separate from TDF which is on interval 1. We are currently testing cells from a number of additional patients who have inherited different portions of the Y chromosome to pinpoint the mapping more closely. It is of interest that in mouse a Y-linked gene controlling spermatogenesis (Spy) maps near Hya on the Sxr fragment: they could be the same or closely linked genes. In man, a gene controlling spermatogenesis maps to Yq and the data so far do not exclude that it could be coincident with the H-Y gene.

scholarly journals Large-Scale Prospective T Cell Function Assays in Shipped, Unfrozen Blood Samples: Experiences from the Multicenter TRIGR Trial

2013 ◽  
Vol 21 (2) ◽  
pp. 203-211 ◽  
Author(s):  
David Hadley ◽  
Roy K. Cheung ◽  
Dorothy J. Becker ◽  
Rose Girgis ◽  
Jerry P. Palmer ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Function ◽  
Dependent Diabetes Mellitus ◽  
Biochemical Tests ◽  
Blood Draw ◽  
Blood Samples ◽  
Cell Functions ◽  
Cell Counts ◽  
T Cell Function ◽  
Human T Cell

ABSTRACTBroad consensus assigns T lymphocytes fundamental roles in inflammatory, infectious, and autoimmune diseases. However, clinical investigations have lacked fully characterized and validated procedures, equivalent to those of widely practiced biochemical tests with established clinical roles, for measuring core T cell functions. The Trial to Reduce Insulin-dependent diabetes mellitus in the Genetically at Risk (TRIGR) type 1 diabetes prevention trial used consecutive measurements of T cell proliferative responses in prospectively collected fresh heparinized blood samples shipped by courier within North America. In this article, we report on the quality control implications of this simple and pragmatic shipping practice and the interpretation of positive- and negative-control analytes in our assay. We used polyclonal and postvaccination responses in 4,919 samples to analyze the development of T cell immunocompetence. We have found that the vast majority of the samples were viable up to 3 days from the blood draw, yet meaningful responses were found in a proportion of those with longer travel times. Furthermore, the shipping time of uncooled samples significantly decreased both the viabilities of the samples and the unstimulated cell counts in the viable samples. Also, subject age was significantly associated with the number of unstimulated cells and T cell proliferation to positive activators. Finally, we observed a pattern of statistically significant increases in T cell responses to tetanus toxin around the timing of infant vaccinations. This assay platform and shipping protocol satisfy the criteria for robust and reproducible long-term measurements of human T cell function, comparable to those of established blood biochemical tests. We present a stable technology for prospective disease-relevant T cell analysis in immunological diseases, vaccination medicine, and measurement of herd immunity.

Recombinant CD95-Fc (APG101) prevents graft-versus-host disease in mice without disabling antitumor cytotoxicity and T-cell functions

Blood ◽  
2013 ◽  
Vol 121 (3) ◽  
pp. 556-565 ◽  
Author(s):  
Natalie Hartmann ◽  
Joanna J. Messmann ◽  
Frank Leithäuser ◽  
Maxi Weiswange ◽  
Michael Kluge ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Cell Function ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cell Functions ◽  
T Cell Function

Abstract Graft-versus-host disease (GVHD) induced by transplant-derived T cells represents a major complication after allogeneic bone marrow transplantation (BMT). However, these T cells support engraftment, early T-cell immunity, and mediate the graft-versus-tumor (GVT) effect. Cytotoxic effector functions by transplanted T cells are predominantly mediated by the perforin/granzyme and the CD95/CD95L system. APG101, a novel recombinant human fusion protein consisting of the extracellular domain of CD95 and the Fc domain of an IgG1 antibody inhibited CD95L-induced apoptosis without interfering with T-cell function in vitro and was therefore tested for its ability to prevent GVHD in murine BMT models across minor or major histocompatibility barriers. Starting APG101 treatment either 1 day before or 6 days after transplantation effectively reduced clinical GVHD and rescued survival between 60% and 100% if GVHD was CD95L mediated. APG101 did not interfere with the GVT effect, because P815 mastocytoma and most importantly primary Bcr-Abl–transformed B-cell leukemias were completely eradicated by the alloantigen-specific T cells. Phenotype and homing of alloantigen-specific T cells or their perforin/granzyme-mediated cytotoxicity and proliferative capacity were not affected by APG101 treatment suggesting that APG101 therapy might be useful in GVHD prophylaxis without impairing T-cell function and most importantly preserving GVT activity.

CD4+ T-cell clones specific for wild-type factor VIII: a molecular mechanism responsible for a higher incidence of inhibitor formation in mild/moderate hemophilia A

Blood ◽  
2003 ◽  
Vol 101 (4) ◽  
pp. 1351-1358 ◽  
Author(s):  
Marc Jacquemin ◽  
Valérie Vantomme ◽  
Cécile Buhot ◽  
Renaud Lavend'homme ◽  
Wivine Burny ◽  
...  
Keyword(s):  
T Cell ◽  
Factor Viii ◽  
Mhc Class Ii ◽  
Hemophilia A ◽  
Cd4 T Cell ◽  
Wild Type ◽  
T Cell Clones ◽  
Mhc Molecules ◽  
Cell Clones ◽  
C1 Domain

Mild/moderate hemophilia A patients carrying certain mutations in the C1 domain of factor VIII (FVIII) have a higher risk of inhibitor occurrence. To analyze the mechanisms responsible for inhibitor development in such patients, we characterized FVIII-specific CD4+ T-cell clones derived from a mild hemophilia A patient carrying an Arg2150His substitution in the C1 domain and who presented with a high titer inhibitor toward normal but not self-FVIII. All T-cell clones recognized synthetic peptides encompassing Arg2150. The peptides were presented to the T-cell clones by DRB1*0401/DRB4*01 or DRB1*1501/DRB5*01. Interestingly, the latter haplotype was previously reported as being associated with an increased incidence of inhibitor formation. Peptide I2144-T2161 also bound to other DR molecules such as DRB1*0101 and DRB1*0701, indicating that the peptide binds to major histocompatibility complex (MHC) class II molecules expressed in more than 60% of the population. None of the T-cell clones recognized recombinant FVIII carrying the substitution Arg2150His, even when FVIII was presented by an FVIII-specific B-cell line. The mutation likely alters T-cell recognition of the mutated peptide associated to MHC molecules, because the mutated peptide bound to immunopurified DR molecules nearly as effectively as the native peptide. These observations demonstrate that T cells of this patient with mutation Arg2150His distinguish between self- and wild-type FVIII and provide a plausible mechanism for the frequent occurrence of an inhibitor in patients carrying this substitution. A similar phenomenon may occur with other mutations associated to an increased incidence of inhibitor formation.

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