Leukaemia/Drosophila homology.
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Amino Acid Sequence↗
Biomedical subjects
F Calabi
Publications and source records attributed to F Calabi.
Expression of CD1 in the mouse thymus.
The CD1 antigens are a family of differentiation antigens found predominantly, but not exclusively, in the human thymus. Although three antigens (CD1a-c) are described by monoclonal antibodies, five genes (CD1A-E) are found in the human genome. The cloning of the mouse CD1 genes (Bradbury, A., Belt, K.T., Nery, T.M., Milstein, C. and Calabi, F., EMBO J. 1988. 7:3081) demonstrated the presence of homologues to human CD1D, but not to any of the other human CD1 genes. In this work we have examined the expression of mouse CD1D mRNA in the thymus and shown that it is predominantly cortical, as is the expression of the CD1 antigens in man. Somewhat surprisingly, we also find that most CD1D mRNA in the mouse thymus is unspliced. Despite this, we have also been able to show, using a polyclonal antiserum directed against a bacterial fusion protein, the existence of the expected protein product.
Animals↗
Two classes of CD1 genes.
Herein, we report the DNA sequence of two human CD1 genes, R2 and R3, distinct from those encoding the CD1a, -b and -c antigens. Both genes appear to have an exon/intron structure analogous to the previously analyzed CD1 genes and to be functional on the basis of their sequence. Analysis of the variability patterns, potential intramolecular interactions and predicted secondary structure profile on an alignment of all known CD1 alpha chains suggest some shared structural features with major histocompatibility complex class I molecules in the alpha 1 domains but substantial differences in the alpha 2 domains. Sequence comparison shows that, while R2 is most related to CD1a, -b and -c, albeit to a somewhat lower degree than the latter are to themselves, R3 is more homologous to mouse than to human CD1, suggesting the existence of two functional classes within the CD1 gene family. We propose to retain the non-committal R2 and R3 names until the putative antigens have been identified and their tissue distribution has been established.
Amino Acid Sequence↗
The rabbit CD1 and the evolutionary conservation of the CD1 gene family.
A comparison of the genes encoding the CD1 leucocyte differentiation antigens in man and mouse shows important differences which prompted us to analyze the CD1 genes of the rabbit. We have found that the rabbit genome contains multiple CD1 loci. Upon cloning and sequencing, one of these loci was found to encode the known rabbit CD1-like antigen (R-Ta) and to be closely related to the human CD1b gene, which is absent in the mouse, while a second rabbit gene is closely related to both the human R3 and the mouse CD1 genes. The data reinforce the notion of the existence of two classes of CD1 genes, one of which is conserved in all species, while the other, albeit also evolutionarily old, has been deleted in mice as well as in other rodents.
Amino Acid Sequence↗
Sequence of a rat immunoglobulin gamma 2c heavy chain constant region cDNA: extensive homology to mouse gamma 3.
The complete sequence of the rat immunoglobulin gamma 2c heavy chain constant region has been determined by cDNA cloning and by mRNA sequencing. Comparison with other heavy chain genes reveals a high degree of homology (87%) to mouse gamma 3 and suggests that rat and mouse gamma genes separated from a common set of three ancestral genes.
Amino Acid Sequence↗
Mouse CD1 is distinct from and co-exists with TL in the same thymus.
Human CD1 antigens have a similar tissue distribution and overall structure to (mouse) TL. However recent data from human CD1 suggest that the mouse homologue is not TL. Since no human TL has been conclusively demonstrated, we have analysed the murine CD1 genes. Two closely linked genes are found in a tail to tail orientation and the limited polymorphism found shows that, as in humans, the CD1 genes are not linked to the MHC. Both genes are found to be equally transcribed in the thymus, but differentially in other cell types. The expression in liver, especially, does not parallel CD1 in humans. This demonstrates conclusively that CD1 and TL are distinct and can co-exist in the same thymus. It is paradoxical that despite the structural similarity between mouse and human CD1, the tissue distribution of human CD1 is closer to TL. The possibility of a functional convergence between MHC molecules and CD1 is discussed.
Amino Acid Sequence↗
Structure and expression of the human thymocyte antigens CD1a, CD1b, and CD1c.
The CD1 human antigens are a family of at least three components, CD1a, CD1b, and CD1c, that are characteristic of the cortical stage of thymocyte maturation. CD1a was originally named HTA1 or T6 and thought to be the human equivalent of mouse Tla. The genes coding for all three have now been identified by transfection into mouse cells. The transfectants express the surface antigens that can then be recognized by the corresponding cluster of monoclonal antibodies used to define the three members of CD1. The full sequence of the genomic DNA is described for all three. The intron-exon structure of CD1a is deduced by comparison with a near-full-length cDNA clone. Similar structures are proposed for the other two, largely based on sequence homology. An unusually long 5'-untranslated exon (280 bases long) is highly conserved between the three genes, suggesting an important but unknown function. CD1c has a duplicated form of this exon that is thought to be spliced out. The major homology between the three antigens is in the beta 2-microglobulin-binding domain. The general relatedness to major histocompatibility complex class I and class II molecules is significant but low, with no section of higher homology to mouse Tla.
Amino Acid Sequence↗
Isolation of CD1 genes: a family of major histocompatibility complex-related differentiation antigens.
CD1 differentiation antigens are defined by a group of monoclonal antibodies that characterize immature human thymocytes. A cloned cDNA has been used to identify CD1 genes in a human genomic library. Five CD1 genes have been isolated, and Southern blot analysis suggests that these represent all the cross-hybridizing human CD1 genes. They share a highly conserved exon, which is homologous to the beta 2-microglobulin-binding domain (alpha 3) of major histocompatibility complex (MHC) class I antigens. In this domain, amino acid sequences are 71-88% homologous. However, the homology between CD1 and MHC class I alpha 3 domains is only 21%. This is the same degree of homology as between either of them and the class II beta 2 domain, which does not bind beta 2-microglobulin. The evolutionary implications of these results are discussed.
Antigens, Differentiation, T-Lymphocyte↗
Chromosome translocation activates heterogeneously initiated, bipolar transcription of a mouse c-myc gene.
In many mouse plasmacytomas, the active c-myc gene has been truncated by chromosome translocation with the resultant severance of the protein-coding sequence from the normal promoter. Transcripts of such truncated c-myc genes were analyzed by Northern blotting, nuclease S1 mapping, primer extension assays and cDNA cloning. We conclude that transcription originates from multiple initiation sites on both c-myc coding and non-coding strands with the two-sets of transcripts derived from adjacent but essentially non-overlapping regions located greater than 1 kb from the translocation junction. In X63Ag8, where c-myc is translocated to the immunoglobulin C gamma 2b gene, the c-myc non-coding strand transcripts include the translocation junction and then splice directly into the gamma 2b CH1 exon. We propose that chromosome translocation activates a cryptic promoter in the first intron and that the heterogeneously initiated, bipolar transcription reflects the absence of a suitably placed TATA box element.
Animals↗
Microfingerprinting analysis of human Ia molecules favours a three loci model.
Alpha subunits from DC1 Ia molecules, when compared with DR alpha subunits, are shown to possess distinctive features revealed by differences in microfingerprinting patterns after peptic digestion. Alpha chains from BR4X7 molecules differ from DC1 alpha chains and are more similar to DR alpha chains. Since DC1 and BR4X7 beta chains (which carry the HLA-controlled alloantigenic determinants) associate with different alpha subunits, it is considered unlikely that they are controlled by alleles at the same locus. The proposed model implies the existence of three tightly linked HLA loci controlling the beta subunits of DR, DC and BR molecules respectively.
Alleles↗
Is beta t a component of HLA-A,B,C in thymus derived cells?
beta t, the 12,000 molecular weight polypeptide originally found in HTA 1, a thymus specific differentiation antigen, is a major labelled component of surface iodinated HLA-A,B,C purified by monoclonal antibody W6/32 from the T leukaemia cell line Molt 4. A correlation between the amount of beta t in HLA-A,B,C and the level of HTA 1 expression in Molt 4 and variants derived from it was established. The presence of beta t in the HLA-A,B,C complexes is not due to cross contamination with HTA 1. However, analysis of a large scale HLA-A,B,C preparation using Coomassie blue staining shows that, under conditions of surface iodination, beta t is over-represented by a factor of about 100 times relative to beta 2 microglobulin. The significance of beta t as a minor component of HLA-A,B,C in thymus derived cells remains uncertain.
Antigens, Differentiation, T-Lymphocyte↗
MLR-specific suppressor T lymphocytes in man. II. Functional and membrane characteristics of a specific MLR suppressor subpopulation.
Human MLR-specific suppressor T lymphocytes were induced by in vitro cultivation of human peripheral T lymphocytes in the presence of soluble HLA-DR alloantigens isolated from normal serum. The suppression is specific in that responder cells autologous to the suppressor cells respond to allogeneic stimulating cells that express the same HLA-DR specificity as that recovered from serum and used to induce the suppressor cells. This antigen-specific suppressor T cell population could be divided into suppressor and non-suppressor subpopulations as a function of adherence to a 6MB Sepharose immunoadsorbent coated with the inducing HLA-DR soluble antigen. As a consequence of activation by soluble DR antigen, the suppressor T lymphocyte population as well as the column-enriched suppressor subpopulation express new membrane specificities that can be recognized by antisera from pluriparous women. The specificities that are recognized are not found on autologous, unstimulated B and T cells, nor do they appear to recognize conventional HLA-A,B,C or DR determinants.
Antigens, Surface↗
Human Ia molecules carrying DC1 determinants differ in both alpha- and beta-subunits from Ia molecules carrying DR determinants.
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Antibodies↗
Reciprocal chromosome translocation between c-myc and immunoglobulin gamma 2b genes.
Specific chromosome translocations have been observed in transformed cell lines of both man and mouse and may be implicated in the origin or maintenance of malignancy. In mouse plasmacytomas, translocations have been identified that bring the immunoglobulin alpha heavy-chain gene (C alpha, normally located on chromosome 12) into proximity with c-myc (normally located on chromosome 15), c-myc being the mouse cellular homologue of the avian myelocytomatosis virus transforming gene (v-myc). Here we identify a DNA rearrangement in a mouse hybridoma that has brought c-myc close to C gamma 2b and show that this rearrangement occurred by reciprocal chromosome translocation, as recombinant clones were isolated from the same cell line in which a rearranged variable-region (VH) gene has been brought close to 5' c-myc sequences. The translocation has resulted in the net loss of 7 base pairs (bp) of chromosome 15 sequence as well as in the presence of an additional base of unknown provenance. This reciprocal translocation was analysed in DNA from a mouse hybridoma cell line but is shown to be characteristic of the X63Ag8 myeloma parent.
Animals↗
Serum beta 2-microglobulin binds to a T-cell differentiation antigen and increases its expression.
The human T-cell leukaemia and differentiation antigen HTA 1 is defined by the monoclonal antibody NA1/34 (ref. 1) and also recognized by the monoclonal antibody OKT6. Like class I products of the human major histocompatibility complex, it has a glycosylated heavy (alpha) chain of approximately 45-50,000 molecular weight (MW) in non-covalent association with beta 2-microglobulin (beta 2m) (MW 11,900). A particular feature of HTA 1 is the presence in significant amounts of an additional beta 2m-like subunit, called beta t (refs 3, 4). Top facilitate biochemical studies we have prepared a high HTA 1 expressor variant (NH17) of the human thymoma line MOLT-4. The N-terminal amino acid sequence of the beta t purified from this cell line was shown to be indistinguishable from that of bovine beta 2m. Further, beta t was present when the cells were grown in medium containing fetal calf serum (FCS), but absent from cells grown with human serum (HuS). We show here that addition of human and bovine beta 2m to MOLT-4 and NH17 cells grown in serum-free medium produces a significant elevation of HTA 1 antigen expression, providing evidence for a regulatory or stabilizing function for the exchange of extracellular beta 2m with a cell-surface antigen.
Amino Acid Sequence↗
A novel family of human major histocompatibility complex-related genes not mapping to chromosome 6.
Thymocyte antigens CD1 [Thy,gp45,12] are thought to be the human counterparts of mouse thymus leukaemia (TL) antigens. Serological and biochemical analyses indicate that at least three subsets exist, the first of which (HTA 1/T6) was initially identified by the monoclonal antibody NA1/34. Like TL, CD1 are expressed on cortical thymocytes as well as on some lymphoid neoplasias, and resemble in structure major histocompatibility complex (MHC) class I antigens. However HTA 1/T6 is loosely associated with beta 2-microglobulin and is also found linked by a disulphide bridge to CD8(T8). A molecular genetic approach is needed to investigate the CD1 system, to clarify its relationship to TL antigens and to understand its regulation. We report the isolation of complementary DNA (cDNA) clones encoding a CD1 antigen. These clones reveal a novel family of genes which are MHC-related but are neither equivalent to mouse TL antigens nor linked to the MHC.
Amino Acid Sequence↗