EXPRESSION OF “FOREIGN” CLASS I MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) MOLECULES ON EXPERIMENTAL TUMORS AND THE INDUCTION OF ACTIVE SPECIFIC CANCER IMMUNOTHERAPY

1994 ◽  
pp. 176-199
Author(s):  
Kam M. Hui
Keyword(s):  
Major Histocompatibility Complex ◽  
Cancer Immunotherapy ◽  
Class I ◽  
Major Histocompatibility ◽  
Experimental Tumors ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Specific Cancer

scholarly journals Characterization of a Murine Cytomegalovirus Class I Major Histocompatibility Complex (MHC) Homolog: Comparison to MHC Molecules and to the Human Cytomegalovirus MHC Homolog

1998 ◽  
Vol 72 (1) ◽  
pp. 460-466 ◽  
Author(s):  
Tara L. Chapman ◽  
Pamela J. Bjorkman
Keyword(s):  
Major Histocompatibility Complex ◽  
Heavy Chain ◽  
Class I ◽  
Major Histocompatibility ◽  
Class I Mhc ◽  
Endogenous Peptides ◽  
Β2 Microglobulin ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Infected Cells

ABSTRACT Both human and murine cytomegaloviruses (HCMV and MCMV) down-regulate expression of conventional class I major histocompatibility complex (MHC) molecules at the surfaces of infected cells. This allows the infected cells to evade recognition by cytotoxic T cells but leaves them susceptible to natural killer cells, which lyse cells that lack class I molecules. Both HCMV and MCMV encode class I MHC heavy-chain homologs that may function in immune response evasion. We previously showed that a soluble form of the HCMV class I homolog (UL18) expressed in Chinese hamster ovary cells binds the class I MHC light-chain β2-microglobulin and a mixture of endogenous peptides (M. L. Fahnestock, J. L. Johnson, R. M. R. Feldman, J. M. Neveu, W. S. Lane, and P. J. Bjorkman, Immunity 3:583–590, 1995). Consistent with this observation, sequence comparisons suggest that UL18 contains the well-characterized groove that serves as the binding site in MHC molecules for peptides derived from endogenous and foreign proteins. By contrast, the MCMV homolog (m144) contains a substantial deletion within the counterpart of its α2 domain and might not be expected to contain a groove capable of binding peptides. We have now expressed a soluble version of m144 and verified that it forms a heavy chain–β2-microglobulin complex. By contrast to UL18 and classical class I MHC molecules, m144 does not associate with endogenous peptides yet is thermally stable. These results suggest that UL18 and m144 differ structurally and might therefore serve different functions for their respective viruses.

scholarly journals Immunogenicity and tolerogenicity of self-major histocompatibility complex peptides.

1990 ◽  
Vol 172 (5) ◽  
pp. 1341-1346 ◽  
Author(s):  
G Benichou ◽  
P A Takizawa ◽  
P T Ho ◽  
C C Killion ◽  
C A Olson ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Class Ii ◽  
Class I ◽  
Major Histocompatibility ◽  
Autoreactive T Cells ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Self Tolerance

Mechanisms involved in self-antigen processing and presentation are crucial in understanding the induction of self-tolerance in the thymus. We examined the immunogenicity of determinants from major histocompatibility complex (MHC) molecules that are expressed in the thymus and have tested peptides derived from the polymorphic regions of class I and class II molecules. We found that two peptides corresponding to NH2 termini of the class II alpha and beta chains (Ak alpha 1-18 and Ak beta 1-16) could bind to self-Ak molecules with high affinity and, surprisingly, were immunogenic in that they could elicit strong proliferative T cell responses in B10.A mice (Ak, Ek). Neonatal injection of peptide Ak beta 1-16 resulted in complete unresponsiveness to this peptide at 8 wk of age showing that these T cells were susceptible to tolerance induction. We have also tested certain class I MHC peptides and showed that some can interact efficiently with class II MHC peptides to induce an autoreactive T cell proliferative response. Among these class I peptides is one (Dd 61-85) that has the capacity to bind to self-Ia without being immunogenic, and therefore represents an MHC determinant that had induced thymic self-tolerance. We conclude that some self-MHC molecules can be processed into peptides that can be presented in the context of intact class II molecules at the surface of antigen-presenting cells. Autoreactive T cells recognizing optimally processed self-peptide/MHC complexes are eliminated during development, whereas other potentially autoreactive T cells escape clonal inactivation or deletion. Incomplete tolerance to self-antigens enriches the T cell repertoire despite the fact that such T cells may eventually become involved in autoimmune disease.

scholarly journals Recognition of class I major histocompatibility complex molecules by Ly-49: specificities and domain interactions.

1996 ◽  
Vol 183 (4) ◽  
pp. 1553-1559 ◽  
Author(s):  
J Brennan ◽  
G Mahon ◽  
D L Mager ◽  
W A Jefferies ◽  
F Takei
Keyword(s):  
Major Histocompatibility Complex ◽  
Nk Cell ◽  
Cell Subset ◽  
Family Type ◽  
Class I ◽  
Target Cells ◽  
Major Histocompatibility ◽  
Binding Assays ◽  
Mhc Molecules ◽  
Histocompatibility Complex

Ly-49 is a family type II transmembrane proteins encoded by a gene cluster on murine chromosome 6. One member of this family, Ly-49A, is expressed by a natural killer (NK) cell subset, binds to class I major histocompatibility complex (MHC) molecules, and blocks the killing of target cells bearing the appropriate H-2 antigens. Here we show that another member of this family which is expressed by an NK cell subset, Ly-49C, recognizes H-2b and H-2d structures which are distinct from and overlapping with those recognized by Ly-49A. Interactions between Ly-49A and C and their class I ligands are entirely blocked by the antibodies 5E6, YE1/48, YE1/32, and A1, all of which were found to recognize epitopes contained within the carbohydrate recognition domain (CRD). However, cell-cell binding assays revealed that class I binding specificity is conferred by a combination of sequences within both the CRD and a 19-amino acid adjacent region. We also investigated the question of whether Ly-49A and C form dimers on cells which express both receptors. When coexpressed on COS cells, sequential immunoprecipitation demonstrated that these receptors pair exclusively as homodimers, with no evidence for heterodimeric structures. These observations provide insight into both the biochemical nature of the Ly-49 family as well as the receptor functions of Ly-49C on NK cells.

scholarly journals Ly-49 mediates EL4 lymphoma adhesion to isolated class I major histocompatibility complex molecules.

1994 ◽  
Vol 179 (3) ◽  
pp. 1011-1015 ◽  
Author(s):  
K P Kane
Keyword(s):  
Major Histocompatibility Complex ◽  
Gene Transfection ◽  
Negative Regulator ◽  
Class I ◽  
Major Histocompatibility ◽  
Cell Surface Molecule ◽  
Class I Mhc ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
T Lymphomas

Ly-49 is a recently identified cell surface molecule expressed on a subpopulation of natural killer (NK) cells and certain T lymphomas. It has been suggested, based on gene transfection and antibody blocking studies, that Ly-49 is a negative regulator of NK lytic activity, possibly through an interaction with target cell class I molecules. However, it has not been demonstrated that class I molecules indeed serve as ligands for Ly-49. We have found that T lymphomas expressing Ly-49 bind isolated class I major histocompatibility complex (MHC) molecules but not class II molecules immobilized on plastic. Adhesion to class I molecules was not found with T lymphomas lacking Ly-49 expression. The Ly-49 expressing EL4 lymphoma bound Dd, Dk, and Kb, but not Kd, Kk, or Db, thus demonstrating a restricted pattern of class I adhesion. The observed cell adhesion was class I density dependent, and binding to Dd and Dk was extensively inhibited by the A1 monoclonal antibody directed against Ly-49. These results provide direct evidence for Ly-49 serving as a receptor for a subset of class I MHC molecules.

scholarly journals The Recognition of the Nonclassical Major Histocompatibility Complex (MHC) Class I Molecule, T10, by the γδ T Cell, G8

1997 ◽  
Vol 185 (7) ◽  
pp. 1223-1230 ◽  
Author(s):  
Michael P. Crowley ◽  
Ziv Reich ◽  
Nasim Mavaddat ◽  
John D. Altman ◽  
Yueh-hsiu Chien
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Mhc Class I ◽  
Class I ◽  
Γδ T Cell ◽  
Major Histocompatibility ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Mhc Class I Molecule ◽  
T Cell Clone

Recent studies have shown that many nonclassical major histocompatibility complex (MHC) (class Ib) molecules have distinct antigen-binding capabilities, including the binding of nonpeptide moieties and the binding of peptides that are different from those bound to classical MHC molecules. Here, we show that one of the H-2T region–encoded molecules, T10, when produced in Escherichia coli, can be folded in vitro with β2-microglobulin (β2m) to form a stable heterodimer in the absence of peptide or nonpeptide moieties. This heterodimer can be recognized by specific antibodies and is stimulatory to the γδ T cell clone, G8. Circular dichroism analysis indicates that T10/β2m has structural features distinct from those of classical MHC class I molecules. These results suggest a new way for MHC-like molecules to adopt a peptide-free structure and to function in the immune system.

scholarly journals Genetic Variability of the Major Histocompatibility Complex Class I Homologue Encoded by Human Cytomegalovirus Leads to Differential Binding to the Inhibitory Receptor ILT2

2005 ◽  
Vol 79 (4) ◽  
pp. 2251-2260 ◽  
Author(s):  
Mar Valés-Gómez ◽  
Mitsunori Shiroishi ◽  
Katsumi Maenaka ◽  
Hugh T. Reyburn
Keyword(s):  
Major Histocompatibility Complex ◽  
Nk Cells ◽  
Mhc Class I ◽  
Human Cytomegalovirus ◽  
Class I ◽  
Inhibitory Receptor ◽  
Major Histocompatibility ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Virus Isolates

ABSTRACT Human cytomegalovirus carries a gene, UL18, that is homologous to cellular major histocompatibility complex (MHC) class I genes. Like MHC class I molecules, the protein product of the UL18 gene associates with β2-microglobulin, and the stability of this complex depends on peptide loading. UL18 protein binds to ILT2 (CD85j), an inhibitory receptor present on B cells, monocytes, dendritic cells, T cells, and NK cells that also recognizes classical and nonclassical MHC molecules. These observations suggest that UL18 may play a role in viral immune evasion, but its real function is unclear. Since this molecule has similarity with polymorphic MHC proteins, we explored whether the UL18 gene varied between virus isolates. We report here that the UL18 gene varies significantly between virus isolates: amino acid substitutions were found in the predicted α1, α2, and α3 domains of the UL18 protein molecule. We also studied the ability of several variant UL18 proteins to bind to the ILT2 receptor. All of the variants tested bound to ILT2, but there were marked differences in the affinity of binding to this receptor. These differences were reflected in functional assays measuring inhibition of the cytotoxic capacity of NK cells via interaction with ILT2. In addition, the variants did not bind other members of the CD85 family. The implications of these data are discussed.

scholarly journals Molecular comparisons of the β2-microglobulin-binding site in class I major-histocompatibility-complex α-chains and proteins of related sequences

1991 ◽  
Vol 277 (2) ◽  
pp. 359-369 ◽  
Author(s):  
V A Tysoe-Calnon ◽  
J E Grundy ◽  
S J Perkins
Keyword(s):  
Major Histocompatibility Complex ◽  
Gene Product ◽  
Contact Region ◽  
Class I ◽  
Major Histocompatibility ◽  
Alpha Chain ◽  
Mhc Molecules ◽  
Contact Sites ◽  
Contact Points ◽  
Histocompatibility Complex

beta 2-Microglobulin (beta 2m) binds non-covalently to the alpha 1, alpha 2 and alpha 3 domains of the alpha-chain of Class I major-histocompatibility-complex (MHC) molecules. On the basis of the crystal structures of human leucocyte antigens HLA-A2.1 and HLA-Aw68.1, we have used molecular-graphics analyses to define 44 contact points between 19 alpha-chain residues and 18 beta 2m residues. In 88 other alpha-chain sequences from the HLA-A, HLA-B, HLA-C, HLA-D, HLA-E, HLA-F and HLA-G locus products in man and the H-2, Qa and Tla loci in mouse, 37 contact sites were conserved to 90% or more, and in beta 2m sequences from seven other species 40% of contact sites were totally conserved. Four distinct regions form the contact points between the alpha-chain and beta 2m, one on each of the alpha 1 and alpha 2 domains and two on the alpha 3 domain. We have further studied the alpha-chain sequences of three non-MHC molecules, human CD1 and rat Fc receptor (FcRn), known to bind to beta 2m, and a third molecule, the putative product of the H301 (UL18) gene of human cytomegalovirus (CMV). CMV has been shown to bind beta 2m, and it has been postulated that the H301-gene product, which has sequence similarity to Class I HLA, is the protein responsible. These sequences exhibited much lower residue conservation with the MHC-linked group, although the alpha 3 domain was the most highly conserved, and gaps and insertions were required for optimal alignments with the 90 alpha-chain sequences. Of the 44 beta 2m-alpha-chain contacts defined for Class I HLA, 24 alpha-chain contact sites were conserved in CD1, 25 in FcRn and 17 in the H301-gene product. For CD1 and FcRn, the majority of the conserved beta 2m contacts were found in the alpha 2 domain and the major contact region in the alpha 3 domain. Together with the use of secondary-structure predictions, it was concluded that the binding of beta 2m in CD1 and FcRn was MHC-like at the alpha 3 domain, and probably also at the alpha 2 domain for FcRn, but non-MHC-like for the alpha 1 domain of both molecules and the alpha 2 domain of CD1. In the H301-gene product sequence, only the beta 2m contacts with the main region of the alpha 3 domain were noticeably conserved.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals HHV-7 U21 exploits Golgi quality control carriers to reroute class I MHC molecules to lysosomes

2020 ◽  
Vol 31 (3) ◽  
pp. 196-208
Author(s):  
Aaron T. Dirck ◽  
Melissa L. Whyte ◽  
Amy W. Hudson
Keyword(s):  
Quality Control ◽  
Major Histocompatibility Complex ◽  
Viral Protein ◽  
Class I ◽  
Major Histocompatibility ◽  
Class I Mhc ◽  
Complex Molecules ◽  
Mhc Molecules ◽  
Histocompatibility Complex

U21 is a viral protein that forms hetero-oligomers with class I major histocompatibility complex molecules and reroutes them to lysosomes. It is shown that U21 exits from the Golgi in a distinct clathrin-independent carrier that also carries unfolded and aggregated proteins to lysosomes.

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