Donal B. Murphy

Recognition of the product of a novel MHC TL region gene (27b) by a mouse γδ T cell receptor

The gamma delta T cell receptor (TCR) derived from the mouse KN6 T cell hybridoma recognizes an autologous determinant encoded by a broadly expressed gene mapping in the TL region of the major histocompatibility complex (MHC). We have cloned the gene and demonstrated that it is a novel class I gene (designated 27b) belonging to a hitherto undescribed TL region gene cluster in strain C57BL/6. The BALB/c allele of 27b, gene T17c, is defective because it lacks an appropriate splice acceptor site, which explains the lack of recognition of BALB/c stimulator cells by the KN6 cells. We propose that gamma delta TCR and nonclassical MHC and MHC-related class I molecules have coevolved to recognize a conserved set of endogenous and foreign determinants.

Recognition of MHC TL Gene Products by γδ T Cells

We have studied the ligand specificity of a gamma delta T-cell receptor (TCR) derived from a mouse T-cell hybridoma (KN6). KN6 cells reacted with syngeneic (C57BL/6) cells from various origins (splenocytes, thymocytes, peritoneal exudate cells, etc.) and cells from many different mouse strains. KN6 reactivity against cells from a panel of congenic and recombinant mouse strains demonstrated that the ligand recognized by KN6 is controlled by an MHC-linked gene that most probably maps in the TL region. We cloned this gene and formally proved that it does map in the TL region. This gene turned out to be a novel class I gene (designated T22b) belonging to a hitherto unidentified cluster of TL region genes in strain C57BL/6. This gene was expressed in many different tissues and cell types. We also examined the tissue expression of several other TL genes. One of these, the structural gene (T3b) encoding the thymus leukemia (TL) antigen from C57BL/6 mice, was specifically expressed in the epithelium of the small intestine. Since the intestinal epithelium of the mouse is known to be the homing site for a subset of gamma delta T cells (i-IEL) bearing diverse TCR with V7 rearranged gamma chains, we propose that the T3b gene product is part of the ligand recognized by some of the i-IEL. Our data support the idea that gamma delta T cells might be specific for non-classical class I or class I-like molecules and suggest that gamma delta TCR and non-classical MHC co-evolved for the recognition of a conserved set of endogenous or foreign peptides.

Revised nomenclature of mouse H-2 genes

The H-2 nomenclature was last revised in 1974 (Klein et al. 1974; Shreffler et al. 1974). Since then it has gradually gone out of step with the advances in molecular biology of the H-2 complex as well as the rules for genetic nomenclature established by the International Committee for Mouse Genetic Nomenclature (Lyon 1989). Furthermore, multiple symbols are currently in use designating the same H-2 genes or their products. The present proposal rectifies the existing inconsistencies in the H-2 nomenclature while preserving as much as possible from the previous proposals.

Diversity, Development, Ligands, and Probable Functions of γδ T Cells

The most critical step in the vertebrate immune response is the recognition of antigens by lymphocytes. This task is accomplished by two sets of glycoproteins, immunoglobulins and T cell antigen-receptors (TCRs). The most extraordinary feature of these proteins is their structural variability, much of which originates from the ability of the encoding gene segments to undergo somatic rearrangement.1 All TCRs were initially thought to be composed of a heterodimeric protein composed of α and β subunits. However, the search for the genes encoding these polypeptides led to the identification of a third rearranging gene2,3 which was later shown to code for one of the two subunits of another heterodimeric, TCR γδ.4–6

Multiple sites of crossing over within the Eb recombinational hotspot in the mouse

The Eb gene of the mouse major histocompatibility complex (MHC) contains a well-documented hotspot of recombination. Twelve cases of intra-Eb recombination derived from the b, d, k and s alleles of the Eb gene were sequenced to more precisely position the sites of meiotic recombination. This analysis was based on positioning recombination breakpoints between nucleotide polymorphisms found in the sequences of parental haplotypes. All twelve cases of recombination mapped within the second intron of the Eb gene. Six of these recombinants, involving the k and s haplotypes, mapped to two adjoining DNA segments of 394 and 955 base pairs (bp) in the 3′ half of the intron. In an additional two cases derived by crossing over between the d and s alleles, breakpoints were positioned to adjoining segments of 28 and 433 bp, also in the 3′ half of the intron. Finally, four b versus k recombinants were mapped to non-contiguous segments of DNA covering 2.9 kb and 1005 bp of the intron. An analysis of the map positions of crossover breakpoints defined in this study suggests that the second intron of the Eb gene contains a recombinational hotspot of approximately 800–1000 bp which contains at least two closely linked recombinationally active sites or segments. Further examination of the sequence data also suggests that the postulated location for the recombinational hotspot corresponds almost precisely to an 812 bp sequence that shows nucleotide sequence similarity to the MT family of middle repetitive DNA.

T cell mediated immunosuppression

Suppressor T cells down-regulate the activity of other cells in the immune system, and, albeit controversial, are believed to play a role in immunological tolerance and immunoregulation. Significant progress has been made in characterizing suppressor T cells and their receptors, and in elucidating mechanisms of immunosuppression. This knowledge is important for understanding the immune system and certain disease states and for favorably manipulating immunity.