Nucleotide sequence of mutant I-Aβbm12 gene is evidence for genetic exchange between mouse immune response genes

McIntyre, Katherine; Seidman, J. G.

doi:10.1038/308551a0

Cited by 176 publications

(85 citation statements)

References 31 publications

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“…In addition, five 18-bp synthetic oligonucleotide primers homologous to conserved regions of the known AP and DQO sequences (8,(11)(12)(13)(14) were constructed and used to obtain sequence information on portions of the clones inaccessible from the EcoRI ends (Fig. 1, B-H (18,19), suggesting that it may be an area readily subject to such occurrences. A second notable region is that from nucleotides 115-123 (encoding amino acids [12][13][14] in the (31 domain (Fig.…”

Section: Methodsmentioning

confidence: 99%

Sequence analysis and structure-function correlations of murine q, k, u, s, and f haplotype I-A beta cDNA clones.

Estess¹,

Begovich²,

Koo³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

100

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domain variability is clustered into three discrete regions, two of which divide the Ap chains into subgroups, suggesting an evolutionary history for the separation of alleles in inbred strains of mice. The amino acid sequences of these five chains are compared to each other and to previously published I-Ap chains. Correlations are made between the primary structural differences and the serologic and immune response characteristics mapping to the I-A subregion.The intimate relationship between I-region associated (Ia) antigens and immune responsiveness to a multitude of natural and synthetic antigens has been known for some time (1, 2).Recent studies using either anti-Ia antisera or monoclonal antibodies to block immune responses strongly suggest that Ia antigens are the products of immune response (Ir) genes (3-5), but how a limited number of Ia molecules differentially regulate responses to a myriad of antigens is yet to be resolved. It seems likely that their role in the presentation of antigen to imtnunocompetent cells is of fundamental importance and that primary structural alterations in the a and (3 chains of the class II heterodimer result in a failure to present antigen in a configuration appropriate for recognition. These alterations must also account for the multiple epitopes recognized by both anti-Ia antibodies and alloreactive T cells.In an effort to address the nature of primary structural differences among class II molecules and how these differences affect immune responses, we have undertaken the cloning and sequencing of cDNAs encoding I-Ap chains from several mouse haplotypes. This should facilitate the eventual assignment of particular serologic epitopes and restriction elements to specific amino acids in these chains. Such analysis is a first step in designing experiments in which immune responsiveness can be manipulated via structural alterations in Ia molecules and then, perhaps, understood. Clones hybridizing to the human DQp or the murine Al cDNA probes were tested for the presence of restriction enzyme sites consistent with AP but not Ed coding sequences (9). The longest such clones were subcloned into the EcoRI site ofpBR322 and from there into the EcoRI site of M13 mp8 for sequencing. Sequencing was performed by the dideoxysequencing method of Biggin et al. (10). All clones were sequenced using the M13 universal primer (UP) from the EcoRI ends, as shown in Fig. 1. In addition, five 18-bp synthetic oligonucleotide primers homologous to conserved regions of the known AP and DQO sequences (8,(11)(12)(13)(14) were constructed and used to obtain sequence information on portions of the clones inaccessible from the EcoRI ends (Fig. 1, B-H productive (8, 9, 11-17). MATERIALS AND METHODS

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Section: Methodsmentioning

confidence: 99%

Sequence analysis and structure-function correlations of murine q, k, u, s, and f haplotype I-A beta cDNA clones.

Estess¹,

Begovich²,

Koo³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

100

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“…The I-Ap gene of the bml2 mouse differs from that of the wild type at three nucleotide positions, which give rise to three amino acid changes clustered within the first extracellular domain of the Ap molecule (43). Both structural and functional analyses suggest that this mutation is the product of a gene conversion-like event in which a segment of 14 to 42 nucleotides was exchanged between I-Ab , and I-Eb (30,32,44,45,58).…”

Section: * Corresponding Authormentioning

confidence: 98%

Molecular analysis of antigen recognition by insulin-specific T-cell hybridomas from B6 wild-type and bm12 mutant mice.

et al. 1987

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Molecular analysis of the heterodimeric T-cell antigen receptor of insulin-specific class 11-restricted T-cell hybridomas (THys) derived from C57BL/6 (B6) wild-type and B6.C-H-2bml2 (bml2) mutant mice revealed that such T cells use a diverse V gene repertoire. Analysis of three THys that use related V genes, however, showed a number of novel features. (i) Two THys that share major histocompatibility complex restriction use Va genes that are 98.6% homologous. (ii) Two THys sharing the same antigen fine specificity use a particular germ line V,DJ combination. (iii) A 21-base-pair deletion in the 5' segment of the Jp gene occurs in one THy, suggesting a novel mechanism for generating diversity in T-cell antigen receptor I genes. (iv) The first amino acid encoded by N sequences at the V-D junction is conserved in a pair of T cells which recognize identical antigenic epitopes. The implications of these findings for the structural mechanisms underlying major histocompatibility complex-restricted antigen-specific T-celi recognition are discussed.In contrast to the B-cell antigen receptor, immunoglobulin, the T-cell receptor (Tcr) does not react with soluble antigen, but recognizes an as yet undefined cell surface molecular complex. This complex is apparently formed by the association of an antigen fragment with major histocompatibility complex (MHC) class I or class II proteins. The Tcr is thought to interact with a specific site on the MHC molecule, the histotope, while another site of the Tcr is believed to interact with the antigen epitope (for a review, see reference 53). A rigorous test of this hypothesis has awaited the identification of the Tcr proteins and the genes which encode them. Initial biochemical analysis of the Tcr was made possible by the production of monoclonal antiidiotypic antibodies which allowed for the isolation of the Tcr protein. This protein was shown to be a disulfide-linked heterodimer made up of an acidic a chain and a more basic ,3 chain each with an apparent molecular mass of 40 to 50 kilodaltons (1-3, 16, 23, 24, 37, 38, 42, 46, 47). The identification of the genes encoding the Pi chain (12, 19, 26-28, 39, 40, 49, 51, 55, 56, 60), and the a chain (11, 50) has shown a striking organizational and structural similarity to the immunoglobulin genes (33); both consist of variable-and constant-region segments. Three gene segments, variable (V), diversity (D), and joining (J), make up the V segment of immunoglobulin heavy chain and Tcr ,3, while the immunoglobulin light-chain and Tcr a segments consist of V and J elements only. All V genes are rearranged in somatic cells that transcribe the genes. Despite these recent biochemical and genetic analyses, the mechanism by which the Tcr gene products mediate MHC-restricted antigen recognition remains unclear. Transfection experiments by Steinmetz and his collaborators (15) have clearly demonstrated that the a and I genes are sufficient to encode for MHC-restricted T-cell antigen recognition.To study the mechanism(s) of T-cell recognition, we deve...

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“…Singer, Bethesda, MD. The mouse strains used in this study, their H-2 haplotypes, and the structural alterations in the H-2 molecules of the mutant mouse strains are listed in Table I ( [33][34][35][36][37].…”

Section: Methodsmentioning

confidence: 99%

Thymus dictates major histocompatibility complex (MHC) specificity and immune response gene phenotype of class II MHC-restricted T cells but not of class I MHC-restricted T cells.

Kast¹,

Waal²,

Melief³

1984

The Journal of Experimental Medicine

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Athymic H-2b nude mice received grafts from C57BL/6 (Sendai virus and H-Y antigen cytotoxic T lymphocyte [CTL] responder type), bm1 (H-2Kb mutant, Sendai CTL nonresponder type), or bm12 (H-21-A mutant, H-Y CTL nonresponder type) neonates. In observations of the CTL response to H-Y, both recipients and thymus donors were female. All types of thymus engraftment resulted in mature H-2b splenic T lymphocyte surface phenotype in nude hosts. T cell immunocompetence (as measured by major histocompatibility complex [MHC] CTL responses to allogeneic cells) was restored, and induced nonresponsiveness to the MHC determinants of the engrafted thymus in the nude host. The CTL reaction to Sendai virus in both responder type C57BL/6 and nonresponder type bm1 neonatal thymuses allowed maturation of Sendai-specific, H-2Kb-restricted CTL. For the CTL reaction to H-Y, only responder type C57BL/6 thymuses restored the CTL response, whereas this was not achieved with thymuses from nonresponder type bm12 neonatal females. Results of double thymus (B6 and bm12) engraftment excluded the possibility that this latter effect was caused by suppression. In addition, athymic bm1 mice were engrafted with thymuses from either B6 (Sendai CTL responder type) or syngeneic bm1 neonates (Sendai CTL nonresponder type). Again, both types of neonate thymuses restored T cell competence as measured by MHC/CTL responses to allogeneic cells. However, neither responder B6 nor nonresponder bm1 neonate thymus grafts allowed maturation of Sendai-specific CTL. In conclusion, the thymus dictates MHC specificity and immune response gene phenotype of T cells restricted to class II MHC molecules but not of T cells restricted to class I MHC molecules.

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Nucleotide sequence of mutant I-Aβbm12 gene is evidence for genetic exchange between mouse immune response genes

Cited by 176 publications

References 31 publications

Sequence analysis and structure-function correlations of murine q, k, u, s, and f haplotype I-A beta cDNA clones.

Sequence analysis and structure-function correlations of murine q, k, u, s, and f haplotype I-A beta cDNA clones.

Molecular analysis of antigen recognition by insulin-specific T-cell hybridomas from B6 wild-type and bm12 mutant mice.

Thymus dictates major histocompatibility complex (MHC) specificity and immune response gene phenotype of class II MHC-restricted T cells but not of class I MHC-restricted T cells.

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