Finding the T-cell antigen receptor: past attempts and future promise.
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Animals↗
Biomedical subjects
M Kronenberg
Publications and source records attributed to M Kronenberg.
RNA transcripts for I-J polypeptides are apparently not encoded between the I-A and I-E subregions of the murine major histocompatibility complex.
The I-J subregion of the mouse major histocompatibility complex has been reported to encode antigenic determinants expressed by suppressor T cells. Previously, cosmid clones were obtained from mouse sperm DNA that contain all of the sequences between the I-A and I-E subregions, where I-J has been mapped genetically. However, hybridization of these sequences to RNA prepared from several I-J-positive suppressor T-cell hybridomas did not reveal the presence of a transcript. In addition, no rearrangements in this DNA were detected in the suppressor T cells that we have analyzed. Our results indicate that the I-J polypeptides are not encoded between the I-A and I-E subregions of the major histocompatibility complex. We discuss several hypotheses concerning the possible location and expression of I-J genes.
Animals↗
Antibody and MHC genes.
The striking homology relationships, both in sequence and in general organizational features, among the genes encoding antibodies, transplantation antigens and beta 2-microglobulin suggest that these genes are members of a supergene family. It will be interesting to determine whether any of the regulatory strategies displayed by the antibody gene families will also be employed by the MHC gene families. Indeed, the recombinant DNA approach has given us profound insights into the organization and expression of antibody genes. These same techniques are now beginning to unravel the mysteries of the MHC complex. It is clear that the future will require a much closer collaboration between molecular biologists, cellular immunologists, and immunogeneticists to obtain the appropriate reagents and cell lines necessary to expand our understanding of the molecular biology and enzymology of gene expression in these fascinating systems.
Animals↗
Helper and killer T cells do not express B cell immunoglobulin joining and constant region gene segments.
We have analyzed four kinds of T cells for rearrangement and expression of immunoglobulin genes. These cells include: (a) whole thymus; (b) WEHI-22, a T-cell lymphoma; (c) HT-1, an major histocompatibility complex-restricted T helper line; and (d) CTLLi6, an H-2 alloreactive killer cell line. None of the B-cell joining and constant gene segments are rearranged in the T cells. The monoclonal cells do not express any C kappa, C lambda, Cmu or C alpha RNA species. Small amounts of C kappa, C alpha, and Cmu sequences are present in RNA prepared from the thymus, although the significance of this RNA for T-cell antigen receptor synthesis is uncertain. The data support the hypothesis that expression of B-cell joining and C gene segments is unnecessary for T-cell helper and T-cell killer activity.
Animals↗
The structure and genetics of mouse immunoglobulins: an analysis of NZB myeloma proteins and sets of BALB/c myeloma proteins binding particular haptens.
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Amino Acid Sequence↗
Decline in CD28+ T cells in centenarians and in long-term T cell cultures: a possible cause for both in vivo and in vitro immunosenescence.
The dramatic decline in immune function with age, especially in T cell proliferative activity, has been documented extensively in experimental animal models and in clinical studies of the elderly. A similar proliferative decline is also seen in long-term T lymphocyte cultures used to study in vitro cellular senescence. We have compared the peripheral blood T lymphocytes of centenarians and younger controls for the cell surface expression of CD28, a costimulatory molecule that is required for optimal activation and proliferation following engagement of the T cell receptor. Our analysis shows a significant decrease (p < 0.001) in the percentage of T cells expressing CD28 in the elderly cohort, with values ranging from 44% to 90%, as compared to the mean control value of 91%. The decline in the percentage of CD28+ T cells correlates with a reduction in the CD4/CD8 ratio (r2 = 0.695, p < 0.0001). Concommitantly, experiments using an in vitro T cell culture system showed a progressive loss of CD28 expression with culture "age." The concordance of proliferative decline and loss of CD28 in the centenarians and in the in vitro cultures suggest that a Hayflick phenomenon may operate in vivo leading to immunosenescence.
Adult↗
The structure, rearrangement and expression of D beta gene segments of the murine T-cell antigen receptor.
It has been postulated that the variable region of the beta-polypeptide of the murine T-cell antigen receptor is encoded by three distinct germ-line gene segments--variable (V beta), diversity (D beta) and joining (J beta)--that are rearranged to generate a V beta gene. Germ-line V beta and J beta gene segments have been isolated previously. Here we report the isolation and characterization of two germ-line D beta gene segments that have recognition signals for DNA rearrangement strikingly similar to those found in the three immunoglobulin gene families and in V beta and J beta gene segments. The D beta and J beta segments can join in the absence of V beta gene segment rearrangement and these rearranged sequences are transcribed in some T cells.
Animals↗
Rearrangement and transcription of the beta-chain genes of the T-cell antigen receptor in different types of murine lymphocytes.
Rearrangements of T-cell receptor beta-chain genes are usually found on both chromosomal homologues, occurring by both deletional and non-deletional mechanisms. Two constant-region (C beta) genes have been identified previously and at least one is transcribed in every helper or cytotoxic T cell tested, but the choice of C beta gene expression is not correlated with the specialized functions of these T lymphocytes. By contrast, four of five suppressor T-cell hybridomas examined have deleted all known joining (J beta) gene segments and C beta genes and therefore may have antigen receptors encoded by different T-cell receptor gene families.
Animals↗
Gene rearrangement in cells with natural killer activity and expression of the beta-chain of the T-cell antigen receptor.
The mammalian host defence system can be divided broadly into adaptive and non-adaptive immunity. Adaptive immunity is acquired and is mediated by B and T lymphocytes. Non-adaptive immunity is mediated in part by a small subclass of heterogeneous peripheral blood mononuclear cells. This population, termed null cells, consists of haematopoietic precursors and cells mediating natural killer (NK) activity and antibody-dependent cellular cytotoxicity (ADCC). NK cells are a class of non-adherent, non-phagocytic, rapidly cytotoxic lymphocytes which can efficiently lyse a wide variety of tumour cells, virally infected cells and immature cell types of normal origin. Despite the broad range of targets, only a limited number of specificities are thought to be involved in target-cell recognition. Morphologically, NK cells are large granular lymphocytes, but they have been shown to exhibit cell-surface markers characteristic of both T cells and monocytes, raising doubt over their lineage. The recent cloning of the beta-chain of the T-cell antigen receptor has now allowed us to investigate whether some NK cells are T-cell-related. We have examined rearrangement and expression of the beta-chain of the T-cell receptor in cloned murine NK cell lines and fresh murine NK cell populations, and our results support the hypothesis that a subpopulation of NK cells is related to T cells and provide basis for examining whether some NK activity is mediated by a small number of T-cell receptors.
Animals↗
Intrathecal baclofen application in patients with supraspinal spasticity secondary to severe traumatic brain injury.
Intrathecal application of baclofen is considered the treatment of choice in patients suffering from spinal spasticity insufficiently responding to conventional oral antispastic medication. This approach has also been used successfully in cases with spasticity of supraspinal origin. To achieve a good therapeutic response in the latter condition the amount of intrathecal baclofen has to be approximately twice the dosage required in spinal spasticity. We report on 8 patients suffering from supraspinal spasticity due to severe traumatic brain injury. Intrathecal baclofen reduced spasticity in all patients (mean Ashworth Score from 3.9 to 1.6; mean Reflex Score from 4.0 to 1.4). In some cases improvement of motor performance and in one case recovery of bladder function were noted. In two patients focal epileptic seizures with secondary generalization seemed to be associated with the application of baclofen. The local intrathecal application of baclofen has proven to be an effective therapy in otherwise intractable cases of severe supraspinal spasticity.
Acute Disease↗