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PubMed2005

A genome-wide survey of Major Histocompatibility Complex (MHC) genes and their paralogues in zebrafish.

BACKGROUND: The genomic organisation of the Major Histocompatibility Complex (MHC) varies greatly between different vertebrates. In mammals, the classical MHC consists of a large number of linked genes (e.g. greater than 200 in humans) with predominantly immune function. In some birds, it consists of only a small number of linked MHC core genes (e.g. smaller than 20 in chickens) forming a minimal essential MHC and, in fish, the MHC consists of a so far unknown number of genes including non-linked MHC core genes. Here we report a survey of MHC genes and their paralogues in the zebrafish genome. RESULTS: Using sequence similarity searches against the zebrafish draft genome assembly (Zv4, September 2004), 149 putative MHC gene loci and their paralogues have been identified. Of these, 41 map to chromosome 19 while the remaining loci are spread across essentially all chromosomes. Despite the fragmentation, a set of MHC core genes involved in peptide transport, loading and presentation are still found in a single linkage group. CONCLUSION: The results extend the linkage information of MHC core genes on zebrafish chromosome 19 and show the distribution of the remaining MHC genes and their paralogues to be genome-wide. Although based on a draft genome assembly, this survey demonstrates an essentially fragmented MHC in zebrafish.

Animals↗
PubMedDate not supplied

CIITA transformation rescues the apoptotic function of MHC class II in melanoma cells.

BACKGROUND: Cell-surface major histocompatibility (MHC) class II molecules contribute to a molecular, intercellular complex that stimulates T-cells. MHC class II molecules also activate signaling pathways leading to apoptosis. Lack of CIITA, a co-activator of the MHC class II gene promoter, is responsible for lack of MHC class II on most of the MHC class II-negative melanoma cell lines. MATERIALS AND METHODS: We rescued CIITA and MHC class II expression in melanoma cell lines by stable transformation with a CIITA expression vector and assayed for MHC class II-mediated apoptosis. RESULTS: Reconstitution of CIITA in multiple CIITA-negative melanoma lines restores the apoptotic function of melanoma MHC class II. CONCLUSION: Lack of MHC class II transcription, rather than defects in MHC class II protein function or defects in the other components of the MHC class II-stimulated apoptotic pathway, prevents MHC class II-mediated apoptosis in melanoma cells.

Apoptosis↗
PubMed1990

The regulation of expression of MHC products in mice. Factors determining the level of expression in kidneys of normal mice.

Cytokines, especially IFN, have been shown to increase MHC expression above basal levels in many immunologic processes, but their contribution to normal MHC expression is unknown. Environmental stimuli, such as bacterial LPS, may provoke the secretion of cytokines which could influence MHC expression in the normal host. We therefore studied the factors influencing the normal expression of MHC products in mice, by using kidney as a representative nonlymphoid tissue. Considerable variation in MHC expression was observed between otherwise normal individuals by using indirect immunoperoxidase staining and a radiolabeled antibody binding assay. An intact T cell compartment was not necessary for normal levels of expression; in athymic nude mice and mice with severe combined immunodeficiency disease, MHC expression was similar to or greater than that of controls. Neither a course of broad spectrum antibiotics nor genetically determined resistance to LPS influenced the level of normal expression. Mice raised under germ-free conditions, on a chemically defined diet also had similar levels of MHC expression when compared with mice maintained under conventional conditions. However, when germfree mice were placed in a conventional colony, induction of both class I and II MHC products occurred. Thus, although exposure to bacterial flora or other sources of endotoxin was not required for normal MHC expression, a change in flora can up-regulate expression, probably by inducing the secretion of cytokines from non-T cells. Treatment with cyclosporine or anti-IFN antibodies produced, at most, a small reduction in the level of renal MHC expression. Therefore in some mice, a small component of MHC expression may reflect the secretion of cytokines in response to stimuli such as bacterial LPS. However, most MHC expression in nonlymphoid tissues is constitutive and independent of a physiologic IFN response.

Animals↗
PubMed1989

Down-modulation of MHC-I in a CD4+ T cell line, CEM-E5, after HIV-1 infection.

HIV-1 is capable of infecting many different cell types that express the CD4 molecule. In vivo and in vitro this infection is associated with profound immunologic defects. We have examined the effect of HIV-1 infection on the expression of MHC class I (MHC-I) molecules to explore the possibility that this important immune system molecule is perturbed after HIV-1 infection. Our data show that in vitro, HIV-1 infection of CD4+ PBL, and the CD4+ cell lines, CEM-E5, HT, and U937, results in decreased expression of MHC-I molecules on the cell surface. This down-modulation is transient, occurring 18 h after HIV-1 infection of CD4+ PBL and returning to normal expression by 24 h. In CEM-E5, MHC-I down-modulation occurs over the course of days, reaching its greatest decrease (40%) about the time the cells are producing the most virus. Reversal of MHC-I expression to normal levels occurs as viral production decreases. Down-regulation during the time periods examined appear to be specific for MHC-I and does not occur with other cell-surface Ag nor is it caused by selection of a preexisting cell population with low MHC-I expression. Radioimmunoprecipitation of MHC-I protein from CEM-E5 indicated that the decrease of surface MHC-I is caused by decreased total protein secondary to a decrease in the level of mRNA for MHC-I. These decreased levels of MHC-I are biologically relevant because HIV-1 infected CEM-E5 cells are less susceptible to CTL lysis determined by the use of MHC-I cytolytic T cell clones and with the use of cold target-inhibition assay.

Antigens, CD↗
PubMed1993

Improved renal function in mouse kidney allografts lacking MHC class I antigens.

The immunological responses that lead to rejection of organ and tissue transplants are triggered by the recognition of proteins encoded within the MHC. The relative contributions of responses directed toward MHC class I compared with class II in the loss of functional integrity of vascularized organ grafts have been difficult to define. The recent development of technologies which allow the generation of mice in which specific genes have been altered by gene targeting offers a new approach to addressing this question. We examine here the rejection of kidney allografts from mice lacking native MHC class I Ag. These mice were obtained from embryonic stem cells in which the beta 2 microglobulin (beta 2m) gene had been disrupted by homologous recombination. We found a significant improvement in function of renal allografts from MHC class I-deficient donors compared with allografts from donors with normal MHC class I expression. Surprisingly, the improved function of the MHC class I-deficient grafts was not associated with differences in mononuclear inflammatory cell infiltration of these grafts nor in differences in alloreactive proliferative or cytotoxic T cell responses. However, we did find differences in alloantibody response between the groups. Recipients of control allografts produced antibodies against both donor MHC class I and II, whereas recipients of MHC class I-deficient grafts formed alloantibodies primarily against donor MHC class II Ag. These studies confirm that immune responses directed toward donor MHC class I alloantigens contribute to kidney transplant dysfunction in this model. Also, these findings suggest that, at least for renal transplants, genetic manipulations which reduce MHC class I expression may be effective in overcoming some of the effects of MHC incompatibility.

Animals↗
PubMed1998

MHC molecules and lymphocytes: evolutionary perspective.

The classical polymorphic MHC molecules of class I or class II bind peptides derived from the processed cytosolic or endosomal antigens and export them to the cell surface for presentation to the T cell receptors (TcR) of CD8 or CD4 T lymphocytes, respectively. The classical MHC molecules are unstable when peptides are not bound. The MHC-peptide-TcR interactions constitute a molecular basis of thymic selection of the major streams of alpha beta and gamma delta T lymphocytes. The monomorphic MHC class I-like molecules (class Ib) bind peculiar peptides or nonpeptide antigens or can keep proper conformation even without antigenic peptides. They are recognized by the specialized subsets of nonconventional lymphocytes, mainly extrathymic gamma delta T or natural killer (NK) T lymphocytes. The most unorthodox T lymphocytes can see antigens directly without the participation of MHC or MHC-like molecules or can see MHC-like molecules not loaded with peptides. The conventional B2 lymphocytes are indirectly dependent on MHC-peptide-TcR interactions as they can bind the epitopes of native antigens via Ig surface receptors, to be activated they must present the processed antigens via the MHC class II molecules to the Th2 lymphocytes. In contrast, the B1 lymphocytes can be activated directly without cooperation with T cells via MHC molecules. It seems that both MHC molecules and lymphocyte antigen receptors arose by the expansion of Ig-superfamily genes at the early steps of vertebrate phylogeny. The nonconventional T lymphocytes (gamma delta T cells and NK T lymphocytes) and B1 cells which support innate immunity at the body surfaces or cavities as well as the MHC-like molecules might appear earlier, creating a proper microenvironment for development of the conventional T and B2 subsets of lymphocytes.

Animals↗
PubMed1998

Regulation of MHC class I and II gene transcription: differences and similarities.

Major histocompatibility complex (MHC) molecules serve as peptide receptors. These peptides are derived from processed cellular or extra-cellular antigens. The MHC gene complex encodes two major classes of molecules, MHC class I and class II, whose function is to present peptides to CD8+ (cytotoxic) and CD4+ (helper) T cells, respectively. The genes encoding both classes of MHC molecules seem to originate from a common ancestral gene. One of the hallmarks of the MHC is its extensive polymorphism which displays locus and allele-specific characteristics among the various MHC class I and class II genes. Because of its central role in immunosurveillance and in various disease states, the MHC is one of the best studied genetic systems. This review addresses several aspects of MHC class I and class II gene regulation in human and in particular, the contribution to the constitutive and cytokine-induced expression of MHC class I and II genes of MHC class-specific regulatory elements and regulatory elements which apparently are shared by the promoters of MHC class I and class II genes.

Animals↗
PubMed1992

Mouse hepatitis virus A59 increases steady-state levels of MHC mRNAs in primary glial cell cultures and in the murine central nervous system.

Infection of mixed glial cell cultures with mouse hepatitis virus (MHV)-A59 results in an approximately six-fold increase in the level of major histocompatibility complex (MHC) class I mRNA. In situ hybridization of glial cell cultures infected with MHV-A59 again showed enhanced MHC mRNA expression, both in infected and uninfected cells. These results extend our earlier finding that MHC surface antigens are enhanced on astrocytes and oligodendrocytes after MHV-A59 infection and suggest that this enhancement is a result of an increase in the steady-state level of MHC mRNA. We further demonstrate that increases in MHC mRNA occur in the murine central nervous system (CNS) following infection in vivo. Northern blot analysis of RNA from the brains of infected animals showed transient expression of both MHC class I and class II mRNA over the first 14 days of infection. Expression coincided with viral replication and clearance. In situ hybridization of brain sections from infected animals showed that class I and class II expression was widespread throughout all portions of the brain and in uninfected as well as infected cells. Viral RNA, in contrast, was observed in small foci of cells and mostly within the limbic system. Thus enhancement of MHC mRNA was not restricted either to areas of infection or inflammation. The spatial relationship between viral and MHC expression supports our hypothesis that a soluble mediator is involved in the mechanism of the increase in MHC levels. The fact that MHC induction occurs in vivo as well as in vitro suggests MHC may be important in the mechanism of MHV-induced disease.

Animals↗
PubMed1996

Comparative immunocytochemical study of MHC class II expression in human donor pancreas and isolated islets.

Expression of major histocompatibility complex (MHC) molecules by pancreatic islets may influence the survival of pancreas or islet grafts in allogeneic recipients. This study compares the presence of MHC class II (HLA-DP, DQ, DX and DR)-positive cells in 27 pancreases and in 10 isolated islet preparations from human donors. Cells expressing MHC class II were present in all tissues examined as histiocytes located in interstitial areas in both the endocrine and nonendocrine components and as endothelial cells in the nonendocrine part. Endocrine, acinar and duct cells were MHC class II negative. In pancreases from donors under the age of 7 years the frequency of MHC class II-positive histiocytes was only one third of that in adults, and they rarely contained MHC class II-positive endothelial cells. The MHC class II-positive histiocytes were further phenotyped as macrophages positive for LCA and acid phosphatase, or dendritic cells negative for the latter markers. Dendritic cells were frequent in adult organs but rare in organs from donors under 7 years of age. In freshly isolated islet preparations from adult donors, less than 1% of the cells were MHC class II positive. These were identified as resident macrophages and dendritic cells. No MHC class II positive cells were encountered in the islet capillaries. The putative role of MHC class II-positive donor cells in allograft rejection suggests that these differences in MHC class II expression influence the immunogenicity of pancreatic and islet grafts in an age-dependent manner.

Adult↗
PubMed2006

Molecular study of Mhc-DRB in wild chacma baboons reveals high variability and evidence for trans-species inheritance.

The MHC class II genes of many primate species were investigated extensively in recent years. However, while Mhc-DRB genes were studied in Old World monkeys such as rhesus macaques, the Mhc-DRB of baboons was only studied in a limited way. Because of their close anatomical and physiological relationship to humans, baboons are often used as models for reproduction and transplantation research. Baboons are also studied as a model species in behavioural ecology. Thus, identification of MHC genes would provide a foundation for studies of Mhc, biology and behaviour. Here, we describe the use of PCR, cloning, denaturing gradient gel electrophoresis (DGGE) and sequencing to identify Mhc-DRB sequences in wild chacma baboons (Papio ursinus). We amplified the highly variable second exon of baboon Mhc-DRB sequences using generic DRB primers. To validate and optimize the DGGE protocol, four DNA samples were initially studied using cloning and sequencing. Clones were screened using a novel RFLP approach to increase the number of clones identified for each individual. Results from cloning and sequencing were used to optimise DGGE conditions for Mhc-DRB genotyping of the remaining study subjects. Using these techniques, we identified 16 Paur-DRB sequences from 30 chacma baboons. On the basis of phylogenetic tree analyses, representatives of the Mhc-DRB1 and Mhc-DRB5 loci, and 13 different DRB lineages were identified. Evidence for trans-species inheritance of some Mhc-DRB sequences comes from high identity between the new Paur-DRB sequences and sequences from Papio cynocephalus, Macaca mulatta and possibly Galago moholi.

Amino Acid Sequence↗
PubMed2005

Genomic evolution of MHC class I region in primates.

To elucidate the origins of the MHC-B-MHC-C pair and the MHC class I chain-related molecule (MIC)A-MICB pair, we sequenced an MHC class I genomic region of humans, chimpanzees, and rhesus monkeys and analyzed the regions from an evolutionary stand-point, focusing first on LINE sequences that are paralogous within each of the first two species and orthologous between them. Because all the long interspersed nuclear element (LINE) sequences were fragmented and nonfunctional, they were suitable for conducting phylogenetic study and, in particular, for estimating evolutionary time. Our study has revealed that MHC-B and MHC-C duplicated 22.3 million years (Myr) ago, and the ape MICA and MICB duplicated 14.1 Myr ago. We then estimated the divergence time of the rhesus monkey by using other orthologous LINE sequences in the class I regions of the three primate species. The result indicates that rhesus monkeys, and possibly the Old World monkeys in general, diverged from humans 27-30 Myr ago. Interestingly, rhesus monkeys were found to have not the pair of MHC-B and MHC-C but many repeated genes similar to MHC-B. These results support our inference that MHC-B and MHC-C duplicated after the divergence between apes and Old World monkeys.

Animals↗
PubMed2005

MHC-based patterns of social and extra-pair mate choice in the Seychelles warbler.

The existence and nature of indirect genetic benefits to mate choice remain contentious. Major histocompatibility complex (MHC) genes, which play a vital role in determining pathogen resistance in vertebrates, may be the link between mate choice and the genetic inheritance of vigour in offspring. Studies have shown that MHC-dependent mate choice can occur in mammal and fish species, but little work has focused on the role of the MHC in birds. We tested for MHC-dependent mating patterns in the Seychelles warbler (Acrocephalus sechellensis). There was no influence of MHC class I exon 3 variation on the choice of social mate. However, females were more likely to obtain extra-pair paternity (EPP) when their social mate had low MHC diversity, and the MHC diversity of the extra-pair male was significantly higher than that of the cuckolded male. There was no evidence that females were mating disassortatively, or that they preferred males with an intermediate number of MHC bands. Overall, the results are consistent with the 'good genes' rather than the 'genetic compatibility' hypothesis. As female choice will result in offspring of higher MHC diversity, MHC-dependent EPP may provide indirect benefits in the Seychelles warbler if survival is positively linked to MHC diversity.

Animals↗
PubMed2005

MHC-F DNA sequences in bonobo, gorilla and orangutan.

The major histocompatibility complex (MHC)-F class Ib locus shows a limited polymorphism, and the function of its mainly intracellular protein is not clear. We have identified human leucocyte antigen (HLA)-F orthologous DNA sequences in Pongidae in order to study the MHC-F gene evolution and its products' function. HLA-F orthologous cDNA transcripts are found in chimpanzee and in the new primate species studied (bonobo, gorilla and orangutan). Analyses of the predicted amino acid sequences and their comparison with other primate MHC-F proteins show that MHC-F may be a protein with a typical class I structure and that the key residues of the peptide-binding region (PBR) are highly conserved in MHC-F in all studied primates species. Thus, MHC-F conservation along the primate evolution suggests an important role in cellular physiology. It is possible that the MHC-F protein could be involved, together with MHC-G and MHC-E, in the natural killer (NK) cell activity regulation, although rhesus macaque does not express MHC-G and MHC-E orthologues. The evolutionary pathway of the six-base-pair deletion at exon 2 existing in some primates is put forward.

Amino Acid Sequence↗
PubMed2021

The Murine MHC Class II Super Enhancer IA/IE-SE Contains a Functionally Redundant CTCF-Binding Component and a Novel Element Critical for Maximal Expression.

In both humans and mice, CTCF-binding elements form a series of interacting loops across the MHC class II (MHC-II) locus, and CTCF is required for maximal MHC-II gene expression. In humans, a CTCF-bound chromatin insulator termed XL9 and a super enhancer (SE) DR/DQ-SE situated in the intergenic region between HLA-DRB1 and HLA-DQA1 play critical roles in regulating MHC-II expression. In this study, we identify a similar SE, termed IA/IE-SE, located between H2-Eb1 and H2-Aa of the mouse that contains a CTCF site (C15) and a novel region of high histone H3K27 acetylation. A genetic knockout of C15 was created and its role on MHC-II expression tested on immune cells. We found that C15 deletion did not alter MHC-II expression in B cells, macrophages, and macrophages treated with IFN-γ because of functional redundancy of the remaining MHC-II CTCF sites. Surprisingly, embryonic fibroblasts derived from C15-deleted mice failed to induce MHC-II gene expression in response to IFN-γ, suggesting that at least in this developmental lineage, C15 was required. Examination of the three-dimensional interactions with C15 and the H2-Eb1 and H2-Aa promoters identified interactions within the novel region of high histone acetylation within the IA/IE-SE (termed N1) that contains a PU.1 binding site. CRISPR/Cas9 deletion of N1 altered chromatin interactions across the locus and resulted in reduced MHC-II expression. Together, these data demonstrate the functional redundancy of the MHC-II CTCF elements and identify a functionally conserved SE that is critical for maximal expression of MHC-II genes.

Animals↗
PubMed1984

Selection of thymocyte MHC restriction specificity in vitro.

The thymus is critical for the generation of mature T cells with restricted specificity for major histocompatibility complex (MHC) molecules of thymic genotype. The mechanism by which this T cell commitment to self-MHC gene products occurs in vivo prior to the exposure to foreign antigens is unknown. When thymocytes are cocultured with irradiated syngeneic accessory cells, a proliferation of cells specific for self-Class II MHC molecules is observed. This in vitro response is of interest in the context of the physiologic events that occur in the thymus. However, the functional significance of these in vitro proliferating cells, as well as their relationship to antigen-specific, MHC-restricted T cells, has not been defined. Further, whether this in vitro response is capable of influencing the MHC specificity of the thymocytes is unknown. In the work reported here, cells obtained from these cultures were tested for their ability to help a primed B cell antibody response. This approach allowed an analysis of function, antigen and MHC-restriction specificity, and the behavior of these cells upon transfer in vivo. Potent T-helper function was obtained from such cultures for an antigen-dependent, hapten-specific B cell response. When F1 thymocytes were cultured with F1 accessory cells, the T-helper cells recovered could help B cells of both parental MHC haplotypes. However, if the same F1 thymocytes were first cultured with parental accessory cells, they subsequently cooperated only with the corresponding parental or F1 B cells. This MHC restriction was determined by the MHC genotype of the accessory cell in primary culture. Monoclonal antibody blocking studies demonstrated that Ia molecules were critical to this process. Suppression did not account for the observed restrictions. The effector specificity of the T-helper cells could be mapped to the I-A subregion. On adoptive transfer to lethally irradiated hosts, the helper cells could localize to peripheral lymphoid organs. These cells retain their in vitro-imposed restriction specificity even when transferred back to and primed in an F1 environment. Using this experimental protocol, carrier antigen-specific, MHC-restricted priming of these thymic T-helper cells could be detected. These results demonstrate that one can select and amplify functional T-helper cells from cultures of thymocytes whose precise MHC-restriction specificity is determined in vitro.

Animals↗
PubMed1994

MHC control of the naive TCR alpha-chain repertoire.

The naive T cell repertoire is shaped by interactions between developing thymocytes and thymic stroma. Both positive and negative selection involve the clonotypic TCR and MHC molecules carrying self-peptides. Except for the MHC-dependent effects of superantigens on TCR V beta usage; there has been little evidence that the TCR structure of naive T cell varies with the selecting MHC products. To examine this point from another angle, in particular the TCR alpha-chain, we have analyzed alpha-chain usage in a system in which the vast majority of T cells express a transgene-encoded TCR beta-chain, compatible with efficient T cell development on a wide range of MHC haplotypes. Endogenous TCR alpha-chains are thus selected without interference from the forces known to act on TCR-beta, permitting us to observe MHC influences on alpha-chain selection. We have used V alpha-specific Abs to quantitate alpha-chain usage in MHC congenic, MHC recombinant, and MHC transgenic mice and provide evidence that the naive TCR alpha-chain repertoire is under MHC control. The data demonstrate a direct impact of known MHC class II products but also reflect more complex influences, apparently involving other gene products within the MHC. Sequence analysis of differentially selected TCR suggests that selection acts on the entire alpha-chain, including V alpha, J alpha, and the junctional region.

Amino Acid Sequence↗
PubMed2004

Anti-tumor MHC class Ia-unrestricted CD8 T cell cytotoxicity elicited by the heat shock protein gp96.

In Xenopus as in mammals, gp96 stimulates MHC-restricted cellular immunity against chaperoned minor histocompatibility (H) antigens (Ag). In adult Xenopus, gp96 also elicits peptide-specific effectors against MHC class Ia-negative 15/0 tumors. To determine whether gp96 can generate functionally heterogeneous CD8+ effectors (CTL that kill MHC class Ia+ minor H-Ag-disparate lymphoblasts and MHC class Ia- tumor targets), LG-6 isogenetic frogs were immunized with gp96 purified either from MHC-identical but minor H-Ag-disparate LG-15 normal tissues or from the MHC class Ia-negative 15/0 tumor line (derived from LG-15 frogs). LG-15 normal liver-derived gp96 did not induce detectable CD8+ in vitro killing against 15/0 tumor cells. However, 15/0-derived gp96 did induce killing against both MHC class Ia+ LG-15 lymphoblasts and the MHC class Ia- 15/0 tumor, but not against another MHC class Ia- tumor (B3B7) or against LG-6 lymphoblasts. Tumor killing was better when 15/0 rather than normal LG-15 irradiated stimulators were used, but in vitro stimulation without prior in vivo immunization was ineffective. These data suggest that (1) 15/0-derived gp96 chaperones minor H-Ag shared with normal LG-15 lymphocytes and elicits MHC-restricted CTL, and (2) 15/0-derived gp96, but not normal liver-derived gp96, generates CD8+ effectors that kill 15/0 tumor cells in the absence of MHC class Ia expression.

Animals↗
PubMed1996

MHC class I is functionally associated with antigen receptors in human T and B lymphomas.

We have studied the antibody-induced effect of cross-linking the major histocompatibility complex class I (MHC-I) in human T leukemic cells (Jurkat) and human B lymphoma cells (Solubo, Burkitts lymphoma) on intracellular [Ca2+]i levels. The increase in [Ca2+]i after MHC-I cross-linking in Jurkat cells and Solubo cells was dependent on both intra- and extracellular Ca2+ stores. The initial increase was dependent on intracellular stores but the long-term elevated [Ca2+]i level was due to an influx of Ca2+. The kinetics of Ca2+ release and influx was different in the two cell lines. In both cell lines the increase in [Ca2+]i after MHC-I cross-linking caused upregulation of CD69, an early marker of activation. When studying the effect of MHC-I cross-linking on the TCR- and B cell antigen receptor (BCR)- mediated increase in [Ca2+]i, respectively, we observed that MHC-I had a costimulatory effect on the TCR-mediated increase in [Ca2+]i in Jurkat cells but not on the anti-IgM-mediated activity of Solubo cells. Studies of subpopulations of Jurkat and Solubo cells expressing different levels of MHC-I on their cell surfaces revealed that the TCR- and BCR-mediated increases in [Ca2+]i, respectively, were positively correlated with the level of MHC-I expressed on the cell surface. These observations suggest two different roles in signal transduction for the MHC-I molecules in the T and B cells studied. First, by themselves MHC-I complexes are able to induce activation of intracellular second messenger systems following cross-linking. Second, threshold levels for activation through antigen receptors in T and B cells are dependent on or determined by the actual numbers of MHC-I complexes present in the cell membrane. Thus the present data strongly point to a new, physiological role for MHC-I molecules in T and B cells.

Antigens, CD↗