H-40, an antigen controlled by an Igh linked gene and recognized by cytotoxic T lymphocytes. I. Genetic analysis of H-40 and distribution of its product on B cell tumors.

Self Cite

A hallmark of MHC class I antigens is their high degree of polymorphism, which is thought to have been generated by gene conversion and subsequent selection (1). The MHC-restricted T cell recognition of foreign antigens depends on the polymorphic portions of MHC antigens . A mismatch in polymorphic MHC class I loci within a species evokes unusually high levels of alloreactive T cells (2, 3) and complex antibody responses (4), Though there are a number of hypotheses, the basis of this vigorous alloresponsiveness within a species has not been fully elucidated (5).In recent years, efforts have been made to define the sites within an MHC class I antigen that are responsible for eliciting alloreactivity and H-2 restriction . Studies of in vivo-generated H-2Kb mutants (1) and recombinant MHC class I genes engineered in vitro (6-13) have revealed that the first (a-1) and second (a-2) external domains of the molecule, but not the third (a-3) domain, are responsible for alloreactivity and MHC restriction. It has been shown (6-13) that alloantibodies can recognize determinants within a single domain independent of adjacent domains, while most CTL recognize conformational determinants dependent on the interaction of the a-1 and a-2 domains.Unlike other antigenic molecules in which positions of epitopes are well defined (14-16), the precise localization of allodeterminants of an MHC class I antigen has only begun (1, 17, 18) . Previously, we postulated (10) that the region of amino acids 63-73 of the a-1 domain of the H-2Dd (Dd) antigen forms alloantigenic sites to which mAbs specific for the Dd antigen react. This was based on a comparison of the primary amino acid sequences of H-2 antigens and their predicted secondary structures. The role of this region of the MHC molecule in controlling CTL epitopes has been unexplored, largely because all of the in vivoderived H-2 mutant and HLA subtype molecules that have been characterized biochemically do not have alterations between residues 63 and 73 (13).

Section: Methodsmentioning

confidence: 99%

Introduction of H-2Dd determinants into the H-2Ld antigen by site-directed mutagenesis.

Koeller¹,

Lieberman²,

Miyazaki³

et al. 1987

Self Cite

“…Anti-H-2L d CTL clones were generated by limiting dilution as described previously (26). Clones L9.4 and L11.15 were derived from (C3H × BALB/c-dm2)F~ anti-DBA/2 effectors, clones L13D.4A, L13D.8, and L13D.…”

Section: Methodsmentioning

confidence: 99%

Expression and function of a nonglycosylated major histocompatibility class I antigen.

Miyazaki

Appella

Zhao

et al. 1986

Self Cite

The major histocompatibility class I antigens, expressed in most somatic cells, have carbohydrate moieties. We constructed mutant mouse MHC class I genes in which codons for the N-linked glycosylation sites were replaced by those of other amino acids. L cell transformants expressing the nonglycosylated class I antigens allowed us to investigate biological roles of carbohydrates with the highest specificity possible. The nonglycosylated antigen was unchanged in its overall serological specificities, and was recognized by alloreactive cytotoxic T cells. Further, the antigen was capable of mediating cytotoxic activity of vesicular stomatitis virus-specific T cells. These studies indicate that carbohydrates are not essential for immunological function of the MHC class I antigens. Cell surface expression of the nonglycosylated antigen was markedly reduced as compared with the native antigen, which was not attributable to accelerated degradation or rapid shedding. We conclude that the primary role of carbohydrates of the class I antigens is to facilitate the intracellular transport of the nascent proteins to the plasma membrane. The possible involvement of carbohydrate-receptor interactions in this process is discussed.

“…However, given our preliminary evidence (Table V) Lm-1, H-40, and H(C~) may all be members of a genetic complex that codes for a family of lymphoid and macrophage differentiation antigens. Forman et al (2) have found that H-40 expression accompanies surface Ig expression, and have suggested therefore that H-40 is important in B cell function. Given our data on the complexity of the Lm-1 antigen system, the pattern of expression of these antigens and their modulation during lymphocyte activation, it seems likely that the Lm-1 locus is important for the function and interaction of lymphocytes and macrophages.…”

Section: Discussionmentioning

confidence: 99%

Expression of murine Lm-1 locus. Lm-1 determinants on lymphocytes and macrophages, and effects of Lm-1 incompatibility on bone marrow grafts.

O’Toole¹,

Bosma²,

Bosma³

1985

The Lm-1 locus controls the expression of one or more cell surface alloantigens recognized by cytotoxic T lymphocytes (CTL). ~ Earlier studies showed Lm-1 is Igh-linked and located five map units telomeric to Pre-I on chromosome 12 (1). Two Lm-1 alleles (Lm-1 a and Lm-1 b) were identified, and lipopolysaccharide (LPS) blasts from 46 strains derived from crosses between Lm-I a and Lm-1 b mice were typed. 37 of these strains were known to have genetic recombinations in the telomeric region of chromosome 12. None of the recombinations divided the Lm-1 locus; i.e., all strains typed unambiguously as either Lm-I a or Lm-I b. Accordingly, if Lm-I were to consist of more than one gene, such genes would have to be closely linked.Two other laboratories (2, 3) have identified Igh-linked loci for cell surface alloantigens recognized by CTL. Forman et al. (2) have defined a locus telomeric to Igh and Tsu that codes for an antigen (H-40) that is expressed only on surface Ig-positive B cells. The antigen described by Rolink et ai. (3), H(C.), is also encoded by a locus teiomeric to Igh, but is expressed on both B and T lymphocytes.All of the above findings clearly demonstrate that the telomeric end of mouse chromosome 12 codes for cell surface determinants that are immunogenic for T cells. What is not clear, however, is the number of such antigens, their distribution and relationship to each other, and their possible role in cell differentiation and interaction.To elucidate further the nature of Lm-1 and its product(s), we tested different cell types for expression of Lm-1 determinants. We show here that Lm-1 determinants (a) are expressed on T and B cell blasts, some pre-B cell lines, and macrophages, but not on fibroblasts, normal (unstimulated) thymocytes, and cloned lines of two thymic T cell lymphomas; (b) are differentially expressed on