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PubMed1992

An MHC interaction site maps to the amino-terminal half of the T cell receptor alpha chain variable domain.

We have used cloned T cell receptor (TCR) genes from closely related CD4 T cell lines to probe the interaction of the TCR with several specific major histocompatibility complex (MHC) class II ligands. Complementarity determining region 3 (CDR3) equivalents of both alpha and beta TCR chains are required for antigen-MHC recognition. Our data provide novel information about the rotational orientation of TCR-MHC contacts in that exchange of the amino terminal portion of the TCR alpha chain containing the putative CDR1 and CDR2 regions results in both gain and loss of MHC class II specificity by the resulting receptor. These two TCRs differ primarily in recognition of polymorphisms in the second hypervariable region of the MHC class II alpha chain. These results document the involvement of CDR1 and/or CDR2 of the TCR alpha chain in MHC recognition and suggest a rotational orientation of this TCR to its MHC ligand.

Amino Acid Sequence↗
PubMed1987

Cellular expression of MHC glycoproteins on erythrocytes from normal and aneuploid chickens.

The major histocompatibility complex (MHC) in the chicken (B-complex) encodes glycoproteins homologous in function and distribution to the mammalian MHC. These are the B-F (class I) and B-L (class II) glycoproteins. In addition, a third glycoprotein (B-G) is also encoded by the chicken MHC. We are interested in examining gene regulation and cellular expression of these MHC gene products in the chicken. The trisomic line of chickens is being developed as an animal model for this purpose. Birds from this line contain either 2, 3, or 4 MHC-encoding chromosomes. In this study, we investigated the hypothesis that the quantities of B-complex glycoproteins on the membranes of fully differentiated erythrocytes are proportional to the number of MHC-encoding chromosomes present in particular birds. Hemagglutination final titer and quantitative adsorption assays were carried out using erythrocytes from disomic and aneuploid chickens homozygous for the B15 haplotype. The average hemagglutination final titers were higher for tetrasomic cells as compared to disomic cells. Furthermore, in adsorption assays, employing a B15 cross-reacting alloantiserum, trisomic and tetrasomic erythrocytes displayed increased adsorption capabilities (1.6 and 3.1 fold, respectively) compared to disomic control cells. These results indicate a step-wise increase in the amounts of erythrocyte surface glycoproteins per cell in the trisomics and tetrasomics, respectively. Such findings are consistent with a MHC-dosage-dependent model of gene expression in homeothermic vertebrates.

Adsorption↗
PubMed1994

HIV-1 gp41 binding proteins and antibodies to gp41 could inhibit enhancement of human Raji cell MHC class I and II expression by gp41.

Based on our findings, that HIV-1 soluble gp41 could bind to several proteins on the human, T, B and monocyte cells independently of CD4, we examined the effect of HIV-1 soluble gp41 (sgp41;Env amino acids 539-684) on surface expression of MHC I and II, ICAM-1 and CD21 molecules on human Raji cells. Flow cytometry (FACS) analysis demonstrated that sgp41 could selectively enhance MHC class I and II expression on Raji cells, but did not increase expression of other cell surface antigens, such as, CD21 and CD54 (ICAM-1). Soluble gp41 could also enhance MHC class I and II expression on another human B cell line, Bjab. The sgp41-dependent enhancement of the MHC class I and II expression on Raji cells is time- and dose-dependent. The sgp41 enhancement effect on the MHC antigen expression could be inhibited by the sgp41-binding proteins of 45, 49 and 62 kD (isolated from Raji-lysate) which could inhibit the spg41-binding to Raji cells. Interestingly, this sgp41-dependent enhancement of the MHC class I and II expression could also be inhibited by two mAbs to HIV-1 gp41, but not by a third mAb binding to a different site on gp41. These results demonstrate that HIV-1 sgp41 can selectively enhance the human Raji cell MHC class I and II antigen expression and this enhancement effect could be inhibited by the sgp41-binding proteins and anti-gp41 antibodies, and suggest that the sgp41-dependent enhancement is mediated by its binding to Raji membrane proteins of 45, 49 and 62 kD.

Antibodies, Monoclonal↗
PubMed1992

Ontogeny of immunosuppressive activity, MHC antigens and leukocytes in the rat testis.

The levels of immunosuppressive activity and the presence of MHC antigens and leukocytes were studied in the immature and the sexually mature rat testis. The immunosuppressive activities were measured from high-molecular weight (greater than 5 kDa) fractions of testis extracts using the protectin bioassay. The presence of MHC antigens and leucocytes was studied using the indirect immunoperoxidase method. In the immature rats, clusters of class I MHC antigen positive cells and a few cells expressing class II MHC antigen were present in the testicular interstitium. In the sexually mature rats, all the cells were MHC I+, and MHC II+ cells were numerous in the testicular interstitium. The seminiferous epithelium was MHC-negative in both the immature and the sexually mature testis. W3/25+ leukocytes were present in the interstitium and the tubular wall in both the immature and the sexually mature rat testis, but not in the seminiferous epithelium at any age. At 20-30 days of age, the testicular extracts were neutral or slightly stimulated 3H-TdR incorporation into peripheral blood lymphocytes, but at 44-60 days of age they inhibited lymphocyte proliferation significantly. In gel filtration, a peak of immunosuppressive activity was observed at approximately 400 kDa (protectin A) in both 20- and 60-days-old rat testes. A smaller peak was present at approximately 200 kDa in both age groups. This study shows that the testicular immunoregulatory microenvironment is different in the immature and the sexually mature rats. This may be important in such age-dependent human diseases as mumps orchitis and the testicular relapses of acute lymphoblastic leukemia.

Age Factors↗
PubMed1987

Monoclonal antibodies to sheep MHC class I and class II molecules: biochemical characterization of three class I gene products and four distinct subpopulations of class II molecules.

The availability of a panel of monoclonal antibodies to sheep MHC class I and class II gene products has allowed for the first time an assessment of the relative complexity of the sheep MHC. By using four monoclonal antibodies to MHC class I, and seven monoclonal antibodies to MHC class II molecules together with one-dimensional SDS-PAGE, sequential immunoprecipitation and 2-dimensional gel analysis, three class I gene products and four distinct subsets of class II molecules have been identified. Sheep class I molecules showed heterogeneity on 2-dimensional gels and as in mouse and man, represented the products of at least three different non-allelic class I genes. Interestingly, the sheep beta 2 microglobulin molecule also displayed heterogeneity, consistent with either two primary gene products or allelic variation. Four sheep class II monoclonal antibodies identified distinct, non-overlapping subsets of sheep class II molecules of Mr 32-36 K (alpha chain) and 25-28 K (beta chain). These class II molecules were co-expressed on sheep B lymphocytes and represented the primary products of different sheep MHC class II genes. The class II molecules within three of these subsets displayed allelic polymorphism essentially restricted to their beta polypeptides, while the fourth subset of class II molecules showed allelic variation in both their alpha and beta polypeptides. The results of this study represent the first evidence for gene duplication and heterogeneity within the sheep MHC. The identification of three primary class I gene products and four distinct subsets of class II molecules suggests three class I loci and up to four distinct class II subregions within the sheep MHC. Potentially large numbers of allelic variants of these different gene products may be expressed in normal sheep.

Animals↗
PubMed1993

Equine T-lymphocyte MHC II expression: variation with age and subset.

This paper describes the characteristics of a monoclonal antibody (CVS10) that reacts with an equine leukocyte antigen. On the basis of tissue distribution and biochemical characteristics, this antigen is equine MHC II. The equine MHC II antigen was found on a large subset of T-lymphocytes in addition to all B-lymphocytes, as has been reported previously. In addition MHC II was found to be present on a large proportion of both the mutually exclusive equine T-lymphocyte subpopulations which express either the equine homologues of CD4, or CD8. In a study of changes in equine MHC II expression with age it was found that far fewer lymphocytes express MHC II in neonatal foals than in adult horses. An increase with age was demonstrated. This age related change in MHC II expression was shown to occur principally within the T-lymphocyte subpopulation. It is proposed that this change may be associated with the development of a memory T-lymphocyte population, and that MHC II expression may be a marker for memory T-lymphocytes.

Aging↗
PubMed1995

Major histocompatibility complex antigens in normal, acanthotic and neoplastic ovine skin: an association been tumor invasiveness and low level MHC class I expression.

The distribution and density of ovine MHC class I and class II antigens in normal, acanthotic and malignantly transformed ovine skin was investigated using monoclonal antibodies and an immunoperoxidase technique. The subjects were sheep that had been exposed to high levels of sunlight for more than 6 years. The expression of MHC class II antigens in the plasma membrane of cells within the normal epidermis was restricted to basally located dendritic and mononuclear cells. Normal keratinocytes did not express MHC class II antigens. However, we observed low levels of intracellular MHC class II expression in both acanthotic and neoplastic keratinocytes. Expression of MHC class I antigens was variable in normal and acanthotic epithelium; it was usually present, but of low intensity in very early ovine squamous cell carcinoma and was increased in small, but morphologically typical, tumors. Tumors originating on the nose, which are more invasive than those on the ear, were found to express significantly less MHC class I (P < 0.05). Thus, an association between tumor invasiveness and low level expression of MHC class I was apparent. This may have diagnostic value and highlights a mechanism by which neoplastic cells may evade immune surveillance by T cells.

Acanthosis Nigricans↗
PubMed1992

Is the establishing of tolerance to self obligatorily MHC restricted?

The prevailing paradigm used to interpret how T cells recognize antigen treats antigen processing as obligatory because the T cell antigen receptor complex can only detect antigen located in a "groove" found on MHC-encoded restricting elements. The vast majority of experimental systems used to analyze how T cells recognize antigen depend on induced T cells executing their effector functions, and it is agreed without exception that this event is MHC restricted. However, to date, the extrapolation of the obligatory MHC restriction of effector function to the level of the antigen-responsive T cell that makes the tolerance induction decision, depends not on experiment, but on theoretical constructs. The few experiments designed to test whether tolerance is MHC restricted are open to several interpretations, only one of which is consistent with the view that all antigen recognition events must be MHC restricted. If it can be shown that tolerance is not obligatorily MHC restricted, then the pillar of the prevailing paradigm will have fallen. The experiments described here throw into serious doubt the evidence that has been used to conclude that tolerance is obligatorily MHC restricted.

Animals↗
PubMed1992

Locally superantigen-activated peritoneal cytolytic T lymphocytes belong to the CD8+ CD45RC- subset and lyse MHC class II+ tumor cells.

Bacterial encoded superantigens (SA) are capable of activating and targeting cytolytic human and mouse T lymphocytes (CTL) to lyse major histocompatibility complex class II positive (MHC class II+) target cells. In this study both in vitro and in vivo activated rat CTL were directed against MHC II+ tumor targets by bacterial encoded SA. Polyclonal in vitro activation of rat peripheral blood T lymphocytes generated CTL capable of killing MHC class II+ human BSM cells coated by staphylococcal enterotoxin (SE) -A, -E, -D, and TSST-1 but not by SEB or SEC1-3. Allo selective peritoneal CTL generated by intraperitoneal stimulation with allogeneic spleen cells were directed against BSM cells by SEA, -D, and -E but not by SEB, SEC1-3 or TSST-1. Based on the above observations, and in order to locally activate CTL, SEA was chosen for in vivo priming of rats by intraperitoneal inoculation of the toxin. SEA injection generated highly cytolytic CTL, and maximum cytolytic responses were seen at 50-250 micrograms SEA per animal with a peak in response 48-72 hours after injection of the toxin. The cytolytic activity of peritoneal SEA reactive effector cells was confined to the TCR alpha beta+ CD4- CD8+ CD45RC- cell population. MHC class II- colon carcinoma cells were insensitive to lysis by SEA reactive CTL but colon carcinoma cells induced to express MHC class II by interferon-gamma (IFN-gamma) treatment were efficiently lysed in the presence of SEA. Comparison of rat and human MHC II+ colon carcinomas revealed a peak in sensitivity to lysis at 10-100 ng SEA/ml for both tumor targets. These findings suggest that superantigens can be used in local immunotherapy of peritoneal tumors such as ovarian and colorectal carcinomatosis, with inducible or constitutive expression of MHC class II.

Animals↗
PubMed1994

Induction of MHC class II antigen expression on murine microglia by interleukin-3.

The effects of various cytokines on MHC class II antigen expression were examined in murine microglia. Interleukin-3 (IL-3), as well as interferon-gamma (IFN-gamma), induced MHC class II antigen expression on these cells. IL-3 additionally enhanced MHC class II antigen expression induced by IFN-gamma. The induction of MHC class II antigen expression by IL-3 was not mediated via IFN-gamma production, because the effect was not blocked by antibodies to IFN-gamma. In contrast, granulocyte-macrophage colony-stimulating factor (GM-CSF) did not affect the expression of MHC class II antigen on naive cells and down-regulated IFN-gamma-mediated induction of MHC class II antigen expression on microglia. Because IL-3 and GM-CSF are apparently produced in the central nervous system, MHC class II antigen expression on microglia may be regulated by these cytokines synthesized in the central nervous system.

Animals↗
PubMed1994

Major histocompatibility complex class II and III in Addison's disease. MHC alleles do not predict autoantibody specificity and 21-hydroxylase gene polymorphism has no independent role in disease susceptibility.

The major autoantigens in Addison's disease have recently been shown to be members of the adrenal steroidogenic enzymes, such as 21OH. The genes encoding the 21OH enzyme are located in the class III segment of the MHC complex. Therefore, its identification as an autoantigen provides a novel link between MHC and susceptibility to this autoimmune disease. We have determined the MHC class II (DRB1, DQA1, DQB1, DPB1) and class III (TNF, HSP70, C4, 21OH) gene polymorphism in patients with Addison's disease. Also, we tested whether presence of autoantibodies against 21OH is associated with specific alleles in MHC. Our results show that patients with Addison's disease in association with APS2 or Addison's disease as an isolated form share highly similar MHC class II and class III alleles. A very strong association with HLA DRB1*0301, DQA1*0501, DQB1*0201, and DPB1*0101, as well as with the C4A + 21OHA gene deletion and TNFB*1 allele was observed. However, identical gene markers were observed also in controls matched for DRB1*0301, thus suggesting that the patient group did not carry MHC gene segments specific for Addison's disease. The presence of autoantibodies against 21OH was not found to be directly determined by the MHC alleles; rather it was associated with the clinical form of the disease.

Addison Disease↗
PubMed1992

Flow cytometric analysis of tumour infiltrating lymphocyte activation and tumour cell MHC class I and II expression in breast cancer patients.

The primary tumour cells and tumour infiltrating lymphocytes (TILs) of 31 breast cancer patients have been analysed by dual colour flow cytometry to determine whether the phenotype and/or activation status of the TILs bears any relationship to the expression of MHC antigens on the tumour cells. The phenotype and activation status of 5000 TILs were studied using Mabs to CD4, CD8, HLA DR, CD25 (the low affinity inducible IL-2 receptor) and the transferrin receptor and related to Class I and Class II MHC expression on 5000 primary tumour cells. On the tumour cells, Class I MHC expression ranged from 1-74%, averaging 12.9%. HLA DR expression ranged from 1-69% averaging 14.3%. When the phenotypic proportions of the lymphocytic infiltrate were analysed there was found to be a correlation between tumour expression of Class I MHC and the proportion of both CD4+ (P less than 0.05) and CD8+ (P less than 0.02) T cells within the tumour. No such relationship was found with the MHC Class II antigen. When TIL activation markers were analysed, the percentage of CD8+ TILs positive for HLA DR expression correlated strongly with the expression of Class I (P less than 0.001) and Class II (P less than 0.001) antigens on the tumour cells. The percentage of CD4+ TILs positive for HLA DR expression also correlated significantly, but less strongly with the expression of Class I (P less than 0.01) and Class II (P less than 0.02) antigen expression on the tumour cells. The percentage of CD4+ TILs positive for CD25 expression correlated with both Class I (P less than 0.05) and Class II (P less than 0.03) expression on the tumour cells while the percentage of CD8+ TILs positive for CD25 did not. The percentage of TILs bearing the transferrin receptor showed no measurable correlation with the expression of either class of MHC antigen on the tumour. The data suggest that MHC expression on the tumour cells has a selective effect on the response capacity of different parts of the immune system.

Breast Neoplasms↗
PubMed1993

Differential effects of IFN-gamma on kidney cell expression of MHC class II molecules, kidney cell associated molecules and their stimulatory capacity in mixed lymphocyte kidney cell culture.

Mixed cell co-cultures of lymphocytes responding to kidney cells (MLKC), islets of Langerhans (MLIC) and mixed lymphocyte culture (MLC), were used to clarify mechanisms in allogeneic and autoimmune (tissue-associated) antigen presentation. Fresh kidney cortical tubular cells (KC), Madin-Darby canine kidney (MDCK), and dog kidney (6247) (DK) cell lines were used in MLKC reactions, and islets of Langerhans were used in the MLIC as putative antigen presenting cells (APC). The stimulating cells were treated with purified or recombinant dog interferon-gamma (IFN-gamma), and the detection of class II MHC molecule expression was assessed by a moneclonal antibody (mAb) (B1F6). Transcription of MHC class II mRNA and IFN-gamma mRNA was measured by semiquantitative polymerase chain reaction, and detection of a kidney cell (tissue-associated) antigen molecule was assessed by the mAb I1F6 that recognizes 72 and 150 kDa tubular cell protein(s) (KT1). The MDCK cell line constitutively expressed low levels of MHC class II molecules and KT1. The steady-state level of the MHC class II mRNA transcription was virtually unaltered by treatment with IFN-gamma (400 units) for 48 hours; however, the MHC cell surface protein expression was enhanced. The KC and DK cell lines constitutively expressed KT1, but not MHC class II molecules; these cells required a minimum of 4000 units, and a 62-hour incubation with IFN-gamma was needed to upregulate both surface MHC class II molecules and the transcription of corresponding specific mRNA. In the MLKC reaction both the MDCK and DK cell lines, as well as fresh KC cells, could serve as lymphocyte activators. This could be amplified by exogenous IFN-gamma. The removal of APC from the responding T cell population did not reduce the IFN-gamma effect. This indicates that IFN-gamma treatment allows for the expression of all of the co-stimulating factors and/or adhesion molecules necessary for these cells to serve as (surrogate) APC (direct as opposed to indirect antigen presentation). The requirements for purified IFN-gamma to increase this amplification was greater in the MLKC reactions with kidney cells than in the MLC reactions. The mAbs anti-IFN-gamma and I1F6 differed in their ability to inhibit lymphocyte proliferation depending on the different cell types involved. The I1F6 inhibited the MDCK and DK cell-driven MLKC (in the absence of exogenous IFN-gamma).(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed2004

Potential roles of protein oxidation and the immunoproteasome in MHC class I antigen presentation: the 'PrOxI' hypothesis.

The major histocompatibility complex (MHC) class I (MHC-I) antigen presentation system is responsible for the cell-surface presentation of self-proteins and intracellular viral proteins. This pathway is important in screening between self, and non-self or infected cells. In this pathway, proteins are partially degraded to peptides in the cytosol and targeted to the cell surface bound to an MHC-I receptor protein. At the cell surface, T cells bypass cells displaying self-peptides but destroy others displaying foreign antigens. Cells contain several isoforms of the proteasome, but it is thought that the immunoproteasome is the major form involved in generating peptides for the MHC-I pathway. How all intracellular proteins are targeted for MHC-I processing is unclear. Oxidative stress is experienced by all cells, and all proteins are exposed to oxidation. We propose that oxidative modification makes proteins susceptible to degradation by the immunoproteasome. This could be called the protein oxidation and immunoproteasome or 'PrOxI' hypothesis of MHC-I antigen processing. Protein oxidation may, thus, be a universal mechanism for peptide generation and presentation in the MHC-I pathway.

Animals↗
PubMed2005

Recombinant antibodies with T-cell receptor-like specificity: novel tools to study MHC class I presentation.

MHC class I molecules play a central role in the immune response against a variety of cells that have undergone malignant transformation by shaping the T cell repertoire and by presenting peptide antigens from endogeneous antigens to CD8+ cytotoxic T cells. Because of their unique specificity such MHC-peptide complexes are a desirable target for novel approaches in immunotherapy. Targeted delivery of toxins or other cytotoxic drugs to cells which express specific MHC-peptide complexes that are involved in the immune response against cancer or viral infections would allow for a specific immunotherapeutic treatment of these diseases. We have recently demonstrated that antibodies with the antigen-specific, MHC restricted specificity of T cells can be generated by taking advantage of the selection power of phage display technology. In addition to their tumor targeting capabilities antibodies that mimic the fine specificity of T cell receptors can serve as valuable research reagents that enable to study human class I peptide-MHC ligand-presentation as well as TCR-peptide-MHC interactions. T-cell receptor-like antibody molecules may prove to be useful tools for studying MHC class I antigen presentation in health and disease as well as for therapeutic purposes in cancer, infectious diseases, and autoimmune disorders.

Antibodies↗
PubMed2005

Beta2-microglobulin required for cell surface expression of blastocyst MHC.

Blastocyst MHC is a mouse MHC class Ib gene that is selectively expressed in blastocysts and placenta like human HLA-G, which protect fetal trophoblasts and some tumor cells from NK cell attack, and in TAP-dependent expression on the cell surface. We expressed blastocyst MHC cDNA in beta2-deficient EL-4 S3 or beta2m-transfected EL-4 S3 cells. In parental EL-4 S3 cells, only 47-kDa blastocyst MHC protein was expressed and retained in the cytoplasm. However, additional 51-kDa blastocyst MHC protein was expressed on the surface of beta2m-transfected EL-4 S3 cells. The 51-kDa protein was resistant to Endo-H, whereas the 47-kDa protein was sensitive for Endo-H. The results suggested that beta2m as well as TAP was necessary for the transportation of blastocyst MHC from endoplasmic reticulum to cell surfaces through the Golgi apparatus, similar to other MHC class I molecules.

Animals↗
PubMed2006

Dendritic cells regulate exposure of MHC class II at their plasma membrane by oligoubiquitination.

Dendritic cells (DCs) initiate adaptive immune responses by activating T cells via cognate interactions between MHC-peptide complexes and T cell receptors. In immature DCs, MHC class II is predominantly stored in late endocytic compartments, where it has a short half-life because of degradation. In contrast, mature DCs recruit MHC class II to the plasma membrane. We here demonstrate that in immature DCs, the beta-chain of MHC class II was oligoubiquitinated after proteolytic processing of the associated invariant chain in endosomes and that this modification was required for efficient endocytosis and sorting into luminal vesicles of multivesicular bodies. Ubiquitination of MHC class II was suppressed in lipopolysaccharide-activated DCs. Mutated MHC class II lacking its ubiquitination site was expressed at the plasma membrane, irrespective of DC maturation. Together, these data provide a molecular basis for the regulation of MHC class II-mediated antigen presentation by DCs.

Animals↗
PubMed2003

Down-regulation of MHC class II receptors of DH82 cells, following infection with Ehrlichia canis.

In order to evaluate whether infection with E. canis alters the expression of major histocompatibility complex (MHC) class I and/or MHC class II receptors, and by doing so alters the immune response to the organism, flow cytometry was performed on DH82 cells infected with Ehrlichia canis (90% infection) and on uninfected DH82 cells of the same passage, using anti-canine MHC class I and II antibodies. MHC class II expression was evident in 47.6 and 46.2% (mean 46.9%) of uninfected DH82 cells using two different anti-MHC class II antibodies, while no MHC class II expression was evident in DH82 cells infected with E. canis. The present results indicate that infection of DH82 macrophages with E. canis down-regulates their MHC class II receptors. These results suggest a possible mechanism by which E. canis evades the immune system.

Animals↗