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Results for “Major Histocompatibility Complex”

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PubMed2005

Liver sinusoidal endothelial cells have a capacity for inducing nonresponsiveness of T cells across major histocompatibility complex barriers.

Livers transplanted across major histocompatibility complex (MHC) barriers in mice are normally accepted without recipient immune suppression. To identify the cell type that contributes to induction of such a tolerance state, we established an allogeneic mixed hepatic constituent cell-lymphocyte reaction (MHLR) assay. Hepatic constituent cells were isolated from C57BL/6 (B6) and Balb/c mice as stimulators, and splenocytes were isolated from B6 mice as responders. Irradiated hepatic constituent cells were co-cultured with fluorescent dye (CFSE)-labeled B6 splenocytes. In the allogeneic MHLR using either whole hepatic constituent cells or parenchymal hepatocytes as stimulators, a lack of T-cell proliferation was observed. Only when CD105(+) cells, which are exclusively liver sinusoidal endothelial cells (LSECs), were depleted from hepatic constituent cell stimulators, the MHLR resulted in marked proliferation of both allo-reactive CD4(+) and CD8(+) T cells. These results indicate that CD105(+) LSECs have the capacity to induce nonresponsiveness of T cells across MHC barriers.

Animals↗

PubMed1991

Role of diversifying selection and gene conversion in evolution of major histocompatibility complex loci.

Genes at the major histocompatibility complex (MHC) in mammals are known to have exceptionally high polymorphism and linkage disequilibrium. In addition, these genes form highly complicated gene families that have evolved through gene conversion and unequal crossing-over. It has been shown recently that amino acid substitution at the antigen recognition site (ARS) is more rapid than synonymous substitution, suggesting some kind of positive natural selection working at the ARS. It is highly desirable to know the interactive effect of gene conversion and natural selection on the evolution and variation of MHC gene families. A population genetic model is constructed that incorporates both selection and gene conversion. Diversifying selection is assumed in which sequence diversity is enhanced not only between alleles at the same locus but also between duplicated genes. Expressed and nonexpressed loci are assumed as in the class I gene family of MHC, with gene conversion occurring among all loci. Extensive simulation studies reveal that very weak selection at individual amino acid sites in combination with gene conversion can explain the unusual pattern of evolution and polymorphisms. Here both gene conversion and natural selection contribute to enhancing polymorphism.

Alleles↗

PubMed1990

Odor types determined by the major histocompatibility complex in germfree mice.

The major histocompatibility complex (MHC) is the prime but not exclusive determinant of genetically specific constitutive body odors, termed odor types, represented strongly in urine of the mouse. Perception of MHC-determined odor types influences reproductive behavior in the contexts of mate choice and maintenance of early pregnancy, tending to favor the propagation of one MHC type over another. How MHC genotype determines MHC odor type is unknown. One possible explanation is that differential odorants are generated by populations of commensal microorganisms whose composition is somehow geared to MHC diversity. This hypothesis was tested in the Y-maze system in which mice are trained to distinguish the urinary odors of MHC-congenic mice. First, it was shown that mice could readily be trained to distinguish the urines of germfree MHC-congenic mice. Second, it was shown that mice trained to distinguish the urines of conventionally maintained MHC-congenic mice could as readily distinguish the urines of germfree MHC-congenic mice. These results imply that MHC-determined odor types do not depend on odorants generated by microorganisms.

Animals↗

PubMed2004

Differential peptide dynamics is linked to major histocompatibility complex polymorphism.

Peptide presentation by major histocompatibility complex (MHC) molecules is of central importance for immune responses, which are triggered through recognition of peptide-loaded MHC molecules (pMHC) by cellular ligands such as T-cell receptors (TCR). However, a unifying link between structural features of pMHC and cellular responses has not been established. Instead, pMHC/TCR binding studies suggest conformational and/or flexibility changes of the binding partners as a possible cause of differential T-cell stimulation, but information on real-time dynamics is lacking. We therefore probed the real-time dynamics of a MHC-bound nonapeptide (m9), by combining time-resolved fluorescence depolarization and molecular dynamics simulations. Here we show that the nanosecond dynamics of this peptide presented by two human MHC class I subtypes (HLA-B*2705 and HLA-B*2709) with differential autoimmune disease association varies dramatically, despite virtually identical crystal structures. The peptide dynamics is linked to the single, buried polymorphic residue 116 in the peptide binding groove. Pronounced peptide flexibility is seen only for the non-disease-associated subtype HLA-B*2709, suggesting an entropic control of peptide recognition. Thermodynamic data obtained for two additional peptides support this hypothesis.

Entropy↗

PubMed1998

The major histocompatibility complex in fish.

The first major histocompatibility complex (MHC) molecule in fish was identified in 1990 using a polymerase chain reaction strategy with degenerate primers (thereby avoiding the problem of low sequence similarity between higher vertebrates and fish). Since that time, MHC in fish has attracted much attention, partly due to evolutionary aspects and partly because of the potential practical consequences for future fish breeding. Knowledge of the MHC molecules in fish has thus been growing extremely rapidly. All current data point to a functional MHC system in fish. There seem to be many loci and many alleles for both classes of MHC molecules, but a lack of knowledge about functional loci versus pseudogenes and non-classical loci is making it difficult at present to establish the exact number found within each species. Fish create a few surprises, such as the lack of a link between class I and class II regions in at least two teleost species. Data on other molecules which are physically or functionally linked to the MHC genes are currently emerging. To date, no studies have established the functional implications of the MHC molecules in fish but, considering the molecular data available, such an achievement will undoubtedly occur soon. Fish may well offer a unique opportunity for identifying correlations of MHC with resistance or susceptibility to diseases.

Animals↗

PubMed1986

A transcriptional enhancer and an interferon-responsive sequence in major histocompatibility complex class I genes.

The major histocompatibility complex class I antigens play an indispensable role in cell-cell interactions. Perturbation of their expression has been shown to have deleterious physiological consequences, including the escape of transformed cells from immune detection. In an attempt to understand how class I genes are regulated, we dissected the Ld gene to identify potential control regions. By using a test vector containing the simian virus 40 early promoter placed upstream of the bacterial chloramphenicol acetyltransferase (cat) gene, we demonstrated the presence of a transcriptional enhancer within the 5'-flanking region. The sequence is functional in both orientations and has been mapped within 350 base pairs upstream of the Ld transcriptional start site. Although human adenovirus 12 can suppress endogenous class I genes, it cannot down-regulate the activity of the transiently transfected cat gene which has been placed under the control of the Ld enhancer and promoter. Our results suggested that if the human adenovirus 12-induced function regulates the expression of class I genes by a trans mechanism, then its target site must not be within 1.9 kilobases of the 5'-flanking region. Treatment of cells with interferon increases the accumulation of class I transcripts. Expression of the cat gene under the control of the Ld enhancer and promoter also can be up-regulated by interferon. Our study shows that the target sequence required for this enhancement resides, at least in part, within the same 350-base pair segment which contains the transcriptional enhancer.

Adenoviruses, Human↗

PubMed1982

Passive allograft enhancement by subclasses of polyclonal antibodies directed toward restricted regions of the major histocompatibility complex.

Two parameters of enhancing major histocompatibility complex (MHC) antibodies, previously separately studied, namely, Ig class and antigen specificity, have been treated simultaneously. In the experimental model used, Sa 1 tumor cells, indigenous of A/J (H-2a) were grafted on CBA (H-2k) or C57BL/Ks (H-2d) mice. Immune sera specific for the H-2 K/D- or H-2 I coded antigens of the A/J haplotype (anti-Kk, or IAk, IBk, IJk, IEk, or ICd, Sd, Gd, or Dd) and their immunoglobulin fractions (separated on protein A-Sepharose columns) were injected either i.v. or locally as mixture with the challenging Sa 1 cells. Within the limits of the studied system, the following results were obtained: (1) Sa 1 cells do possess Iak antigens at their surface detected by C-dependent cytotoxicity; no ICd, Sd, or Gd products were detected. (2) The bulk of enhancing activity is concentrated in IgG1 anti-K/D antibodies (anti-Dd when Sa 1 was grafted on CBA mice and anti-Kk, on C57BL/Ks). (3) Anti-Iak antibodies have some activity on Sa 1 cells grafted on C57BL/Ks mice. This activity is significant for IgG1 anti-Iak and suggestive for IgG2 of the same specificity. (4) No enhancing activity was detected in the other antibodies: IgG2 anti-Dd, IgG2 anti-Kk, IgG1, or IgG2 anti-ICd, Sd, Gd as well as in fractions containing IgM and IgA antibodies directed against any studied portion of the MHC products. This results are discussed in terms of the mechanisms involved in enhancement.

Animals↗

PubMed1984

Murine streptozotocin diabetes: influences of the major histocompatibility complex, genetic background and blood transfusion.

Major histocompatibility complex-linked immune response genes are thought to influence susceptibility to induction of both human insulin-dependent diabetes and murine streptozotocin-induced diabetes. To clarify this relationship, we administered streptozotocin intravenously in two doses (120 and 240 mg/kg body weight) on days 0 and 14, and monitored blood glucose until day 100 in young adult male mice of differing background genome and/or H-2 complex. In addition, we examined the effect of allogeneic whole blood transfusion on subsequent susceptibility to diabetes. B10 recombinant mice possessing the k allele at the centromeric H-2-K and I-A loci were most susceptible to diabetes induction. Variation in susceptibility of different inbred strains with the same major histocompatibility complex genotype suggested a rôle for non-major histocompatibility complex genes. Blood transfusion delayed the onset, but did not significantly reduce the incidence of, delayed hyperglycaemia. We conclude that, in this murine model, multiple genes within the outside the major histocompatibility complex influence multiple-dose streptozotocin-diabetes susceptibility, and that prior blood transfusion may modulate diabetes induction.

Animals↗

PubMed1989

Human major histocompatibility complex contains genes for the major heat shock protein HSP70.

Little is known as to why a large number of human diseases are influenced by the major histocompatibility complex. In some cases, a direct involvement of the products of the polymorphic class I and class II, aas well as the less variable products of the class III, genes has been proposed. During characterization of the class III region for the presence of additional loci, we have located a duplicated locus encoding the major heat shock protein HSP70 between the complement and tumor necrosis factor genes. The HSP70 loci are 12 kilobases apart and lie 92 kilobases telomeric of the C2 gene. As HSP70 proteins have been linked with a protective role during and after cellular stress, and HSP70 analogues are often presented as antigens in bacterial and protozoal infections, this finding may have major implications with regard to the major histo-compatibility complex and associated diseases.

Amino Acid Sequence↗

PubMed1999

The final maturation of at least some single-positive CD4(hi) thymocytes does not require T cell receptor-major histocompatibility complex contact.

The majority ( approximately 70%) of postselection CD4(+) single-positive (SP) thymocytes are CD8(lo)CD4(hi). These cells express very low levels of CD8, undetectable by flow cytofluorimetric (FCM) analysis, but sufficiently high to allow purification by panning. Unlike the fully mature CD8(-)CD4(hi) thymocytes, which account for the remaining approximately 30% of the SP CD4(+) thymocytes, CD8(lo)CD4(hi) cells are functionally immature and short-lived unless they receive an unidentified maturation signal from the thymus. In this study, we tested the hypothesis that this signal is provided by a T cell receptor (TCR)-major histocompatibility complex (MHC) class II interaction. Using intrathymic transfer, we show that the immature CD8(lo)CD4(hi) cells could complete their intrathymic maturation and populate the peripheral lymphoid organs in the absence of MHC class II (and class I) molecules. Furthermore, in mice devoid of class II (and class I) molecules, the progeny of CD8(lo)CD4(hi) cells was long-lived and functionally reactive to allogeneic class II molecules, although their numbers in the spleen and the mesenteric lymph node were approximately 40-50% lower than those in class II(+) mice 5 mo after transfer. Control experiments demonstrated that the surviving cells did not originate from the contaminating mature thymocytes. These results demonstrate that the final maturation, proliferation, and peripheral survival (up to 5 mo) of at least some postselection CD4(+) SP cells do not require the TCR-MHC class II interaction. They also indicate that the TCR-MHC class II interaction(s) required for the intrathymic development of long-lived CD4(+) SP cells occurs before the CD4(hi) SP stage of development.

Animals↗

PubMed1985

Analysis of immunological tolerance to major histocompatibility complex antigens. I. High frequencies of tolerogen-specific cytotoxic T lymphocyte precursors in mice neonatally tolerized to class I major histocompatibility complex antigens.

Injection of (CBA X A)F1 cells into neonatal CBA mice rendered them tolerant to skin grafts of (CBA X A)F1 origin. Limiting dilution analysis revealed a very low frequency of tolerogen-inducible cytotoxic T lymphocyte precursors (CTL-P) in spleens of tolerant mice. Two in vitro procedures allowed, however, the induction of tolerogen-specific CTL-P of high frequencies in tolerant mice: (a) the "by-pass" activation of spleen cells from tolerant mice by concanavalin A under short-term bulk culture conditions followed by culture of limiting numbers of activated responder cells, and (b) absorption of spleen cells from tolerant mice on monolayers of tolerogen-activated T cells from normal syngeneic mice. Furthermore, spleen cells from tolerant mice, recently challenged with a tolerogen-bearing skin graft, specifically suppressed the activation of tolerogen-reactive splenic CTL-P from normal CBA mice under limiting dilution conditions. These data confirm the presence of tolerogen-specific CTL-P of high frequency in tolerant mice and suggest their functional inactivation through a suppressive mechanism.

Animals↗

PubMed1994

Antigen-specific deletion of cloned T cells using peptide-toxin conjugate complexed with purified class II major histocompatibility complex antigen.

In a previous report, we showed that cloned T cells incubated with soluble, cognate major histocompatibility complex (MHC) II-peptide complex internalized the peptide moiety of the complex. Here, we report antigen-specific deletion of cloned T cells by treatment with soluble, cognate MHC II-(peptide-toxin) complexes. Toxin (doxorubicin or mycophenolic acid) was attached to synthetic AcMBP(1-14)Ala4 peptide, an analog of the natural acetylated NH2-terminal segment, AcMBP(1-14), of rat myelin basic protein (MBP). IAk-restricted, AcMBP(1-14)-Specific AJ1.2 and 4R3.9 cloned murine T cells were killed by IAk-(AcMBP(1-14)Ala4-toxin). No killing resulted from incubating AJ1.2 and 4R3.9 cells with irrelevant MHC II-(peptide-toxin) or treating IEk-restricted, pigeon cytochrome c-specific A.E7 cloned murine T cells with IAk-(AcMBP(1-14)Ala4-toxin). T cell receptor-mediated T cell uptake of the peptide-toxin moiety of relevant complex was blocked by anti-T cell receptor-alpha/beta antibody and by excess toxin-free complex. LD50 determinations revealed that cognate MHC II-(peptide-toxin) killed T cells much more effectively than did peptide-toxin conjugate alone. Finally, T cell uptake of peptide-toxin and intracellular release of toxin occurred after incubation with relevant MHC II-(peptide-toxin) containing radiolabeled toxin. These findings, which provide the first evidence that cloned T cells can be deleted with soluble, cognate MHC II-(peptide-toxin) complexes, may have significant clinical relevance for antigen-specific therapy of autoimmune or other T cell-mediated diseases.

Amino Acid Sequence↗

PubMed1980

Growth and reproduction complex in the rat. Genes linked to the major histocompatibility complex that affect development.

The linkage of the major histocompatibility complex (MHC) and the growth and reproduction complex (Grc) in the rat was studied in an F2 hybrid population generated from female BIL/1 (RT1l-Grc) and male YO (RT1u-Grc+) animals: 1.722 offspring were born, and 1,568 were weaned and studied. The body weights of the offspring segregated with the RT1 haplotype of the MHC, and the RT1l homozygotes were significantly smaller than their RT1l/u and RT1u/u littermates. The growth rate of the RT1l/l animals was approximately the same as that of the BIL/1 animals, and both were significantly less than the growth rates of the RT1l/u, RT1u/u, and YO (RT1u) animals. The testes of the RT1l animals showed an arrest of spermatogenesis at the early pachytene stage of the primary spermatocytes, and they were approximately 1/10 as heavy as the testes of the RT1l/u and RT1u/u animals. The ovaries in females of all three haplotypes had the same weight, but there was a decrease in the number of ova released per cycle in the RT1 l/l animals. The major loss of the RT1l homozygotes, which caused distortion of the phenotypic ratios among the offspring, did not occur in utero but in the early postnatal period before weaning. There were 7/1568 recombinants between the MHC, using the RT1.A antigen as the marker, and the Grc, using small body size (dw-3) as the marker, and 1/1568 recombinant between the loci influencing body size (dw-3) and fertility (ft) of the Grc. These data gave the following map distances (95% confidence levels): RT1.A to dw-3, 0.45 (0.25-0.96) centimorgans and dw-3 to ft, 0.07 (0.04-0.40) centimorgans. A female recombinant was used develop an inbred line carrying the RT1.Al-Grc+ chromosome.

Animals↗

PubMed1986

Variable susceptibility to immune complex glomerulonephritis among mice sharing the same major histocompatibility complex.

Three inbred strains of mice were identified which demonstrated different susceptibilities to induction of immune complex glomerulonephritis (ICGN) despite sharing the same major histocompatibility complex haplotype (H-2k). Groups of mice from each of these three strains, B10.BR, CBA and C3H/HeJ, were injected with one of two different dose schedules of horse apoferritin (HAF) for 4 weeks, after which glomerular morphology, immunoglobulin deposition, and serum anti-HAF antibody levels were examined. With either dose schedule, only those mice which demonstrated a high level antibody response developed ICGN and glomerular immunoglobulin deposition. These results suggest that susceptibility to ICGN in this model is related to the level of antigen exposure and to the magnitude of the antibody response, which is not under strict control of the major histocompatibility complex.

Animals↗

PubMed2001

The major histocompatibility complex of the rat (Rattus norvegicus).

This review of the RT1 complex, the major histocompatibility complex (MHC) of the rat, focuses on genetic, genomic, evolutionary, and functional aspects at the molecular level. The class I, class II, and framework genes are listed. The physical map of the RT1 complex as revealed by analysis of clonal contigs is compared with the human and mouse MHC, and the degree of orthologous relationship is outlined. Elucidation of the RT1 complex provides important information for using the rat as a model of experimental transplantation and complex diseases.

Animals↗

PubMed2006

A long N-terminal-extended nested set of abundant and antigenic major histocompatibility complex class I natural ligands from HIV envelope protein.

Viral antigens complexed with major histocompatibility complex (MHC) class I molecules are recognized by cytotoxic T lymphocytes on infected cells. Assays with synthetic peptides identify optimal MHC class I ligands often used for vaccines. However, when natural peptides are analyzed, more complex mixtures including long peptides bulging in the middle of the binding site or with carboxyl extensions are found, reflecting lack of exposure to carboxypeptidases in the antigen processing pathway. In contrast, precursor peptides are exposed to extensive cytosolic aminopeptidase activity, and fewer than 1% survive, only to be further trimmed in the endoplasmic reticulum. We show here a striking example of a nested set of at least three highly antigenic and similarly abundant natural MHC class I ligands, 15, 10, and 9 amino acids in length, derived from a single human immunodeficiency virus gp160 epitope. Antigen processing, thus, gives rise to a rich pool of possible ligands from which MHC class I molecules can choose. The natural peptide set includes a 15-residue-long peptide with unprecedented 6 N-terminal residues that most likely extend out of the MHC class I binding groove. This 15-mer is the longest natural peptide known recognized by cytotoxic T lymphocytes and is surprisingly protected from aminopeptidase trimming in living cells.

Amino Acid Sequence↗

PubMed1993

Staphylococcus-mediated T-cell activation and spontaneous natural killer cell activity in the absence of major histocompatibility complex class II molecules.

We used major histocompatibility complex class II antigen-deficient transgenic mice to show that in vitro natural killer cell cytotoxicity and T-cell activation by staphylococcal exotoxins (superantigens) are not dependent upon the presence of major histocompatibility complex class II molecules. T cells can be activated by exotoxins in the presence of exogenously added interleukin 1 or 2 or in the presence of specific antibody without exogenously added cytokines.

Animals↗

PubMed1996

A study of complexes of class II invariant chain peptide: major histocompatibility complex class II molecules using a new complex-specific monoclonal antibody.

Complexes of major histocompatibility complex (MHC) class II molecules containing invariant chain (Ii)-derived peptides, known as class II-associated invariant chain peptides (CLIP), are expressed at high levels in presentation-deficient mutant cells. Expression of these complexes in mutant and wild-type antigen-presenting cells suggests that they represent an essential intermediate in the MHC class II antigen-presenting pathway. We have generated a monoclonal antibody, 30-2, which is specific for these complexes. Using this antibody, we have found quantitative differences in CLIP:MHC class II surface expression in mutant and wild-type cells. Our experiments also show that CLIP:MHC class II complexes are preferentially expressed on the cell surface similar to total mature MHC class II molecules. These complexes are found to accumulate in the endosomal compartment in the process of endosomal Ii degradation. Analysis of the fine specificity of the antibody indicates that these complexes have Li peptide bound to the peptide-binding groove.

Amino Acid Sequence↗