Info

In mouse, the vast majority (80-90%) of the £ chain exists as a disulfide-linked homodimer, but can also form heterodimers with the related iq, y and (possibly) 0 chains. This leads to the formation of several isoforms of the mature TCR complex within a single T cell, with the potential for functional variation between forms. Cloning and sequencing predict a structure for £ which is markedly different from that of the CD3 proteins. One feature which £ does share with CD3 subunits is the acidic residue in its transmembrane region. Otherwise, it has a minimal extracellular domain, consisting of only nine amino acids including the cysteine responsible for disulfide linkage, and an intracellular domain with a consensus sequence for ATP binding and multiple (six in mice; seven in humans) tyrosines, whose phosphorylation results in a dramatic apparent increase in Mr to 21 kDa. Intriguingly, ti and 0 derive from the same gene as by alternative mRNA processing, although y is encoded by a separate, though linked, gene. The significance of the T], y and 0 chains is unclear, however, given that t) has been demonstrated to be absent from human T cells.

Study of the assembly of a multisubunit complex such as the TCR is hindered by a number of problems. First, the receptor is built up of several transmembrane proteins and requires translocation of subunits across a membrane for its formation. Therefore, it is difficult to study interactions of purified proteins in solution. Furthermore, all TCR components (excepting n) may need to be present for efficient complex formation. However, the combination of several approaches including the examination of immature T cells and T cell lines, together with the analysis of partial receptor complexes, has provided considerable information.

Thymocytes express CD3y, 8 and e at an early stage in their development, before the TCRa and (3 genes have completed their rearrangements: between days 14 and 16 of mouse fetal thymus development, and from week 10.5 in human fetal thymus. In humans, there is also evidence for expression of the

CD3 genes from week 7 in fetal liver, prior to colonization of the thymus. Thus, the CD3 genes are among the earliest T cell lineage genes to be expressed. Without the antigen-binding heterodimer proteins, immature thymocytes do not express significant levels of surface CD3. Cell lines lacking either TCRa or 3 also fail to deliver CD3 to the cell surface, or do so inefficiently. Mutant cell lines defective in I production express only 5% of normal cell surface receptor levels. Cumulatively, these data indicate that a £2-type receptor requires most, and possibly all, subunits for efficient transport to the plasma membrane.

During assembly of the TCR complex, the individual components form partial complexes, a situation which can be mimicked experimentally when genes for the individual subunits are transfected in various combinations into heterologous cells. Such partial complexes are largely unstable and most are rapidly degraded within the cell before reaching the mid-Golgi, but they can be studied to reveal likely subunit interactions within the mature TCR complex. Thus, observed isolated pairwise combinations are CD3ye, CD38e, but not CD3-yS, which is interpreted as evidence against close contact between the CD3y and 8 chains. Intracellular TCR complex assembly may be aided by the molecular chaperone proteins TRAP and calnexin, which are thought to mediate correct subunit interactions. Whether the TCRa and (3 chains dimerize before association with CD3 molecules may depend on which cells are examined, but in immature double-positive thymocytes this is thought not to occur. Instead, trimeric complexes, a8e and |3ye, form first which then combinc via a(3 dimerization and finally associate with the dimer giving a stoichiometry of afí-ySe,^- This is supported by transgenic mouse experiments which indicate one TCRa, one TCR(3 and two CD3e chains per complex. A model structure for the core receptor based on these data is shown in Figure 1.

Figure 1 A model of the T cell antigen receptor (a(3-Y8e2i;2-type) showing an arrangement of subunits compatible with current data. A transverse section through the plasma membrane is shown. Disulfide bonds between a and 0, and between £ sub-units, are shown as solid lines.
How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Post a comment