Mapping the H-Y gene

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.

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

Journal of Experimental Medicine ◽

10.1084/jem.20021796 ◽

2003 ◽

Vol 198 (1) ◽

pp. 99-109 ◽

Cited By ~ 10

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.

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

Journal of Experimental Medicine ◽

10.1084/jem.158.2.428 ◽

1983 ◽

Vol 158 (2) ◽

pp. 428-437 ◽

Cited By ~ 40

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.

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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 ◽

10.1182/blood-2002-05-1369 ◽

2003 ◽

Vol 101 (4) ◽

pp. 1351-1358 ◽

Cited By ~ 81

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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Human naive and memory CD4+ T cell repertoires specific for naturally processed antigens analyzed using libraries of amplified T cells

Journal of Experimental Medicine ◽

10.1084/jem.20090504 ◽

2009 ◽

Vol 206 (7) ◽

pp. 1525-1534 ◽

Cited By ~ 148

Author(s):

Rebekka Geiger ◽

Thomas Duhen ◽

Antonio Lanzavecchia ◽

Federica Sallusto

Keyword(s):

T Cells ◽

T Cell ◽

Antigen Processing ◽

Cellular Immunotherapy ◽

Maximal Response ◽

T Cell Clones ◽

Naive T Cells ◽

Naïve T Cells ◽

Mhc Molecules ◽

Cell Clones

The enormous diversity of the naive T cell repertoire is instrumental in generating an immune response to virtually any foreign antigen that can be processed into peptides that bind to MHC molecules. The low frequency of antigen-specific naive T cells, their high activation threshold, and the constrains of antigen-processing and presentation have hampered analysis of naive repertoires to complex protein antigens. In this study, libraries of polyclonally expanded naive T cells were used to determine frequency and antigen dose–response of human naive CD4+ T cells specific for a variety of antigens and to isolate antigen-specific T cell clones. In the naive repertoire, T cells specific for primary antigens, such as KLH and Bacillus anthracis protective antigen, and for recall antigens, such as tetanus toxoid, cytomegalovirus, and Mycobacterium tuberculosis purified protein derivative, were detected at frequencies ranging from 5 to 170 cells per 106 naive T cells. Antigen concentrations required for half-maximal response (EC50) varied over several orders of magnitude for different naive T cells. In contrast, in the memory repertoire, T cells specific for primary antigens were not detected, whereas T cells specific for recall antigens were detected at high frequencies and displayed EC50 values in the low range of antigen concentrations. The method described may find applications for evaluation of vaccine candidates, for testing antigenicity of therapeutic proteins, drugs, and chemicals, and for generation of antigen-specific T cell clones for adoptive cellular immunotherapy.

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