The T cell receptor

Although it has long been known that T lymphocytes interact with antigen by way of specific receptors, the identification of such receptors has been accomplished only recently (reviewed in [16]). At least two kinds of receptors are presently known, which are expressed by T cells which most likely belong to different lineages. I shall refer to these as the a/fi and the y/6T cell receptors (TcR s). 

It has been remarked that both V and Vp are somewhat more homologous to VL than to VH in their core structure. However, this does not imply significant differences of the binding site, since, for example, CDR loop lengths are closer to those of VH than to those of V, furthermore, VL dimers do not necessarily pack in a significantly different way front V,-VM [10]. 

The ends of the excised DNA sequence have a unique organization [29] (a) each end consists of two short conserved sequences (a heptamer and a nonamer) which are separated by a spacer (b) the spacer can span either one or two turns of the DNA helix (one- or two-turn type) (c) the heptamer/nonamer sets at the two ends are in inverted orientation with respect to each other (d) the spacers at the two ends are of different type, i.e. one-turn type at one end and two-turn type at the opposite end. 

This organization is shared by all V region loci. Heptamer/nonamer sequences are also conserved across loci, i.e. the same sequences are found in both immunoglobulin and TcR gene segments. This pattern of conservation suggests that these sequences are critical to recombination and that the recombination (joining) machinery has similar requirements in T and B cells. Indeed, this has already been shown to be the case ([30] and Chapter 4). 

The somatic recombination which results in V region assembly introduces diversity by three mechanisms first, different combinations of V, D and J segments second, variability in the position of strand breaks third, template-independent 

---

Percus J K, Percus O E and Perelson A S 1993 Predicting the size of the T-cell receptor and antibody combining region from consideration of efficient self-nonself discrimination Proc. Natl Acad. Sci. USA 90 1691-5... 

AMPK can also be activated by a Ca2+-mediated pathway involving phosphorylation at Thr-172 by the Ca2+/calmodulin-dependent protein kinase, CaMKK 3. CaMKKa and CaMKK 3 were discovered as the upstream kinase for the calmodulin-dependent protein kinases-1 and -IV they both activate AMPK in a Ca2+/ calmodulin-dependent manner in cell-free assays, although CaMKK 3 appears to much more active against AMPK in intact cells. Expression of CaMKKa and CaMKK(3 primarily occurs in neural tissues, but CaMKKp is also expressed in some other cell types. Thus, the Ca2+-mediated pathway for AMPK activation has now been shown to occur in response to depolarization in rat neuronal tissue, in response to thrombin (acting via a Gq-coupled receptor) in endothelial cells, and in response to activation of the T cell receptor in T cells. 

COPD is a chronic inflammatory disease that results from prolonged and repeated inhalation of particles and gases, chronic (or latent) infection or an interaction of these factors. In many cases, the inflammation persists even when the exposure (in most cases smoking) is stopped. Prominent among the infiltrating leukocytes are neutrophils, CD8+ lymphocytes (Co-receptor for the T-cell receptor. CD8+ is specific for the class IMHC protein. It is expressed on the surface of cytotoxic T-cells and natural killer cells.) and CD68+ monocytic cells (A lysosomal antigen. All cells that rich in... 

Inhibition of immunomodulatory cytokines (Fig. 1) Anti-T-cell receptor antibodies Muromonab (OKT3, Orthoclone ) binds to the CD3 complex of the T-cell receptor and induces depletion of T-lymphocytes. It is applied to prevent acute rejection of kidney, liver, and heart allografts. Rapid side effects (within 30-60 min) include a cytokine release syndrome with fever, flu-like symptoms, and shock. Late side effects include an increased risk of viral and bacterial infections and an increased incidence of lymphproliferative diseases due to immunosuppression. 

Cytokines. Figure 1 Inhibition of cytokine synthesis during activation of the specific immune system. The monoclonal antibodies Muromonab and Basiliximab are specific for the CD3 complex of the T-cell receptor, and for the IL-2 receptor on lymphocytes, respectively. Cyclosporin and Tacrolimus inhibit activation of cytoplasmic NF-AT, a transcription factor essential for activation of the IL-2 gene ( NFAT Family of Transcription Factors). Sirolimus interferes with mTOR signaling and inhibits IL-2 dependent proliferation. Red pharmaka, blue target proteins. 

Class IIHLA molecules are expressed on the surface of antigen-presenting cells. They play a key role in presentation of processed linear peptide antigens of at least nine amino acids to T cells. Antigen is bound to the HLA antigen binding cleft formed by the a and 3 chains of the HLA class II molecule. This tri-molecular HLA-antigen complex binds in turn to the variable portion of the T-cell receptor. 

The T cell receptor is a clonotypic, T cell specific surface receptor that mostly recognizes peptides bound to MHC molecules on antigen-presenting cells. 

Wang S, Crute BE, Melnikova IN, Keller SR, Speck NA. Cloning and characterization of subunits of the T-cell receptor and murine leukemia virus enhancer core-binding factor. Mol Cell Biol 1993 13 3324-3339. 

G2. Goorha, R., and Bumin, N., Provocative pattern of rearrangements of the genes for the gamma and beta chains of the T-cell receptors in human leukemias. Proc. Natl. Acad. Sci. U.S.A. 84, 4547-4551 (1987). 

The Major Histocompatibility Complex. The molecules making up the major histocompatibility complex (MHC) were first discovered through their ability to provoke rejection response when tissues from one individual were transplanted to another individual of the same species. Quite apart from the MHC s contribution to the difficulties of transplant surgery, in recent years it has become abundantly clear that the MHC plays a major role in the operation of T cell immunity, particularly in its function of presenting antigen to the T cell receptor. 

The T cell receptor diversity arises by comparable mechanisms, and the a(3 receptor for example may exist in at least 8 x 106 and probably many more different combinations. 

Thymus-derived, or T, lymphocytes also have an immunoglobulin-like surface receptor linked with accessory proteins to form the T-cell receptor (TCR). There are similarities between the BCR and TCR in that the recognition part of the T receptor complex is also a dimer. In most T cells, the dimer consists of a and [3 individual peptide... 

---