Biochemistry and genetics

Lyt-2 and Lyt-3 (murine CD8) are both transmembrane glycoproteins which are encoded by two closely linked genes on murine chromosome 6. Except for a subset of natural killer cells, the expression of murine Lyt-2/3 appears to be restricted to T cells. The molecule is a 70 kDa homo- or hetero-dimer composed of two covalently linked chains: an a chain (32-38 kDa), which expresses epitopes detected by Lyt-2-specific antibodies, and a 0 chain (30-34 kDa), which expresses Lyt-3 epitopes. The Lyt-2 chain is the homolog of the CD 8 chain in humans, which consists of homodimers and multi-mers of this chain. Recently, human CD8(3 genes have been identified that encode a CD 8 monomer corresponding to murine Lyt-3.

The Lyt-2 gene contains five exons. The first encodes a signal peptide and an N-terminal region which shows close homology with IgV k light chain regions, including a cysteine-mediated intrachain disulfide bond. Exons 2-5 encode the spacer region, the transmembrane region and two cytoplasmic regions, CI and C2, respectively. Although there is only a single Lyt-2 gene segment there are two types of Lyt-2 chains, a and a', of slightly different size. The 34 kDa a' chain, found only in mice and expressed preferentially in the thymus, is a truncated form of the a chain resulting from alternative splicing of exons encoding the C-terminal cytoplasmic domain including the p56lck binding site.

There is uneven homology between human and murine CD8 molecules. Human CD8 a and /3 chains are encoded on chromosome 2pl2. The most substantial degree of genetic conservation is found in the transmembrane and cytoplasmic domains, while the least is in the external V gene-like domain. Since there is 70% identity of the class I MHC external domain residues between mouse and human, this degree of divergence in the putative binding regions of CD8 is somewhat surprising. On the other hand, conservation of the C-terminal domain may reflect a requirement for this region to interact with intracellular T cell proteins involved in transmembrane signaling. A comparison of rodent CD8 chains with the a and /3 chains of the T cell receptor (TCR) suggests evolution of these three receptor genes from a common ancestor. Divergence between them may be reflected in the acquisition of intervening sequences between V and J by the TCR genes, resulting eventually in the capacity to rearrange multiple V genes during development. The CD8 gene has lost regions encoding C-region domains but, like TCR, has acquired the capacity to recognize MHC molecules at some point in evolution (Figure 2).

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