Structural comparisons of TL antigens derived from normal and leukemia cells of Tl+ and TL- strains and relationship to genetically linked H-2 major histocompatibility complex products.

Abstract

Comparative tryptic peptide analysis was used to probe the structure of the TL products coded for by normally expressed TL alleles (Tlaa and TlaC haplotypes) and the structure of the TL product on ERLD, a TL+ leukemia occurring in a strain that does not normally express TL antigens (Tiab haplotype). In mice that have the Tid' haplotype, the peptide maps of TL glycoproteins from normal thymocytes and from TL+ leukemias were identical, a finding that is consistent with the indistinguishable serologically defined TL phenotype of these cells. Analysis of the Th product on ERLD leukemia cells (TL phenotype, TL.1,2,4) indicates a single TL glycoprotein species with the TL.4 determinant (restricted to leukemias of Tiab and Tiac haplotypes) coexisting on the same glycoprotein as the TL. 1 determinant (normally expressed by thymocytes of Tiaa haplotype). Comparison of the peptides of the TL product of ERLD and the products of the normally expressed Tid' and TLaC loci showed a high degree of structural similarity (i.e., 70-80%) ofshared peptides. In contrast, the products of the Tlaa, Tlab, and TlaC loci shared relatively few peptides with the products of the K, D, and L loci of the closely linked major histocompatibility complex (15-35%). The TL family, therefore, consists of alleles that are highly homologous. This contrasts with the marked diversity and polymorphism among the alleles of the K, D, and L loci.The TL system of cell surface antigens was discovered almost 20 years ago during studies of mouse leukemia (1). A number of unique features set TL apart from other surface antigenic systems (2). In certain strains of mice (designated TL+ strains), TL has the characteristics of a differentiation antigen, expression being limited to thymocytes and leukemia cells of thymic origin. In other strains (TL-strains), TL is not normally expressed on thymocytes, but can be detected on leukemia cells. The usual explanation given for these findings is that all strains of mice have the genetic information for TL but strains differ with regard to regulatory sequences controlling expression vs. nonexpression of TL on normal thymocytes. Leukemogenesis disrupts this regulatory control of TL in TL-strains, resulting in the expression ofnormally silent TL genes and the anomalous appearance of TL antigens on leukemia cells.Mendelian analysis ofTL expression in normal mice showed that the controlling locus (designated Tla) is closely linked to

Interaction between Kb and Q4 gene sequences generates the Kbm6 mutation.

“…Alleles of the K, D, and L genes, the products of which function as restriction-recognition molecules, are highly diverse (13,28). Alleles of the Qa and TL genes exhibit much more conservation of sequence (20,48). When compared with Qa and TL region loci on the population level, the K, D, and L loci are more polymorphic (11,24).…”

“…This large diversity among alleles is in sharp contrast to that observed at other genetic loci, where alleles usually differ from one another by only a few amino acids. This diversity is also remarkable with regard to the high conservation of Qa-and TL-region genes and their protein products, since limited tryptic peptide and DNA sequencing analyses indicate that alleles in these regions exhibit consid-erably less diversity and polymorphism than alleles in the K and D regions of the H-2 complex (20,24,48).…”

Thymus‐leukemia antigen (TL) as a major histocompatibility complex (MHC) class Ib molecule and tumor‐specific antigen

“…The products of TL genes are glycoproteins with molecular weights of approximately 45,000 daltons [7][8][9] and are expressed on the cell surface with β 2 -microglobulin (β 2 M), but they can be independently expressed transporters associated with antigen processing (TAP). 4,[10][11][12] A recent crystallographical analysis yielded the important finding that T18 d -TL has no antigen-binding groove wide enough to accommodate a peptide or lipid antigen, 13) in contrast to other MHC class Ia and Ib products.…”

“…[1][2][3][4][5] TL genes have overall structures similar to MHC class Ia (classical MHC class I) genes, and show high homology among themselves, but they are only distantly related to other MHC class Ia and Ib genes, indicating the operation of natural selection to preserve the function of TL. 6) The products of TL genes are glycoproteins with molecular weights of approximately 45,000 daltons [7][8][9] and are expressed on the cell surface with β 2 -microglobulin (β 2 M), but they can be independently expressed transporters associated with antigen processing (TAP). 4,[10][11][12] A recent crystallographical analysis yielded the important finding that T18 d -TL has no antigen-binding groove wide enough to accommodate a peptide or lipid antigen, 13) in contrast to other MHC class Ia and Ib products.…”

Additional products of the Tla locus of the mouse.

“…For H-2, representing other class I genes, no products other than the familiar H chain were demonstrable under similar conditions. The class I members ofthe extended major histocompatibility complex of chromosome 17 of the mouse comprise a family ofgenes (H-2; Qa; Tla) that are related to one another in DNA structure (1)(2)(3)(4) and in protein-product [heavy (H)-chain] structure (5,6). The Tla gene or genes, by definition, are expressed only by thymocytes and by a proportion of T-cell leukemias presumably corresponding to the thymocyte phase of T-cell differentiation (7)(8)(9).…”