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Early Studies of the T-Cell Receptor – I
This Sqadia video is the demonstration of The T-Cell Receptor – I. T cells possess a receptor that is Antigen specific and clonally restricted receptor. Discovered long after the BCR. T-cell receptor (TCR) differs from the B-cell antigen binding receptor in important ways. TCR is membrane bound and does not appear in a soluble form like BCR. Most TCRs are specific not for antigen alone but for antigen combined MHC. Purification of the TCR by simple antigen-binding techniques is not possible. The molecule responsible for T-cell specificity is a heterodimer, Composed of either α and β or γ and δ chains. By the early 1980s, investigators had learned About T-cell function and failed in their attempts to identify and isolate its antigen-binding receptor. Reports published in the 1970s led to the discovery of Ig isotypes associated exclusively with T cells (IgT). TCR and Igs do not have common recognition elements encoded by entirely separate gene families. By the early 1970s, immunologists had learned to generate cytotoxic T lymphocytes (CTLs) specific for virus-infected target cells. Two models were proposed to explain the MHC restriction of the T-cell receptor i.e The Dual-Receptor Model and The Altered-Self Model.
Early Studies of the T-Cell Receptor- II
T-Cell Receptors were Isolated by Using Clonotypic Antibodies. Identification and isolation of the T-cell receptor was accomplished by Producing large numbers of Mabs to various T-cell clones and then screening the antibodies to find one that was clone specific, or clonotypic. Using this approach, researchers in the early 1980s isolated the receptor and found that it was a heterodimer consisting of alpha and beta chains. In order to identify and isolate the TCR genes, S. M. Hedrick and M. M. Davis sought to isolate mRNA that encodes the alpha and beta chains from a TH-cell clone. Hedrick and Davis next used a technique called DNA subtractive hybridization, to remove the [32P] cDNA from their preparation that was not unique to T cells. The 2% of the expressed genes that is unique to T cells should include the genes encoding the T cell receptor. Cloning of the unhybridized [32P] cDNA generated a library from which 10 different cDNA clones were identified. One clone showed bands indicating DNA rearrangement in T cells but not in the other cell types.
αβ and δγ T-Cell Receptors: Structure and Roles - I
The domain structures of αβ and δγ TCR heterodimers are strikingly similar to that of the immunoglobulins. Each chain in a TCR has two domains containing an intrachain disulfide bond that spans 60–75 amino acids. The TCR variable domains have three hypervariable regions. In addition to the constant domain each TCR chain contains a short connecting sequence. Following the connecting region is a transmembrane region. Finally, each TCR chain contains a short cytoplasmic tail. αβ and γδ T-cell receptors were initially difficult to investigate because, like all transmembrane proteins, they are insoluble.
αβ and δγ T-Cell Receptors: Structure and Roles - II
The majority of T cells in the human and the mouse express T-cell receptors encoded by the αβ genes. These receptors interact with peptide antigens processed and presented on the surface of antigen-presenting cells. Differences in the antigen-binding regions of αβ and γδ were expected because of the different antigens they recognize but no extreme dissimilarities were expected. The recently completed three-dimensional structure for a γδ receptor reveals significant differences in the overall structures of the two types. The most striking feature of the structure is how it differs from the receptor in the orientation of its V and C regions, the elbow angle between the long axes of the V and C regions. In humans the predominant receptor expressed on circulating γδ cells recognizes a microbial phospholipid antigen. The recruited αβ T cells would presumably display a broad spectrum of receptors. Those with the highest affinity would be selectively activated and amplified to deal with the pathogen.
Organization and Rearrangement of TCR Genes - I
The genes that encode the αβ and δγ T-cell receptors are expressed only in cells of the T-cell lineage. The four TCR loci (α, β, γ , and δ) are organized in the germ line in a manner that is remarkably similar to the multigene organization of the immunoglobulin (Ig) genes. In the mouse, the α-, β-, and γ- chain gene segments are located on chromosomes 14, 6, and 13, respectively. The δ-gene segments are located on chromosome 14 between the Vα and Jα segments. The location of the δ-chain gene family is significant. Mouse germ-line DNA contains about 100 Vα and 50 Jα gene segments and a single Cα segment. The δ-chain gene family contains about 10 V gene segments, which are largely distinct from the Vα gene segments. The organization of the TCR multigene families in humans is generally similar to that in mice, although the number of segments differs.