La estructura financiera de las SOCAPS desde la mirada de sus funcionarios

Peripheral T cells can be divided into two subpopulations by the expression of two cell surface glycoproteins CD4 and CD8 (Swain, 1983). Helper I cells express CD4 and recognise exogenously derived peptide in association with class II MHC molecules, whereas cytotoxic I cells express CD8 and recognise endogenously derived peptides in association with MHC class I molecules. Both CD4 and CD8 associate with the protein tyrosine kinase p56'ck (Ick) and form part of the recognition complex of the IC R . They bind to the MHC molecules in conjunction with the IC R (Figure 1.1) and bring Ick into the signalling complex, acting as coreceptors (Fames, 1989). The CD4 and CD8 coreceptors are involved in both the differentiation and commitment of T cells to either a helper or cytotoxic phenotype in the thymus, and the activation of T cells in the periphery.

CD4 and CD8 are both transmembrane glycoproteins and members of the immunoglobulin gene superfamily, but have few structural similarities despite having a similar coreceptor function. Murine CD4 is a single polypeptide with a molecular weight of 55kDa, expressed as a monomer on the cell surface. It is folded into 4 external Ig-like domains (D1-D4) and has a hydrophobic transmembrane segment and a highly basic and conserved cytoplasmic tail

(Maddon e ta i, 1985; Fames, 1989). The D1 and D2 domains, distal to the cell

membrane, have been shown to interact with a negatively charged loop that protrudes from the membrane proximal p2 domain of the MHC class II molecule

(Konig et a/., 1992). In contrast, CD8 is a di-sulphide bonded heterodimer

composed of two chains, a 38kDa CD8a chain (Lyt-2) and a 30kDa CD8p chain (Lyt-3). Both chains consist of a single amino-terminal external domain that is homologous to the V region of Ig, an extended and highly glycosylated hinge region which contains two cysteine residues close to the cell membrane which form the disulphide bonds, a hydrophobic transmembrane segment and a

highly basic cytoplasmic tail (Fames, 1989). The extracellular domain of CDBa

has been shown to interact with the a3 portion of the MHC class I molecule

(Salter etal., 1990).

The C D B a gene encodes two polypeptide chains, C D Ba and CDBa',

which are generated by a process of alternative splicing of mRNA producing

two polypeptides, C D B a which is encoded by the full length gene and the

tailless CDBa' which lacks the cytoplasmic domain (Zamoyska et a!., 19B5;

Tagawa et a!., 19B6). In thymocyte populations the amounts of C D B a and

CDBa' on the cell surface are about equal, but in peripheral T cells from the

spleen or lymph node very little CDBa' is detectable on the cell surface although

it is found intracellularly (Zamoyska and Fames, 19BB). Although CDB can form

C D B aa homodimers, the majority of CDB molecules on the cell surface of MHC

class I restricted T cells is in the C D Bap heterodimer form. Specific

subpopulations of intestinal yb T cells and natural killer cells express exclusively

the C D B aa homodimer, but these cells are not M HC restricted suggesting

CDBp may have a unique role in the differentiation or function of M HC class I

restricted T cells. In addition unlike CDBa, the C D Bp chain can only be

transported to the cell surface in the heterodimer form (Gorman etal., 19BB).

C D 4 has four external domains and extends approximately 130À

allowing it to interact with the p2 domain of the class II M HC molecule (Figure

1.1). For the CDB molecule to bind to the membrane proximal a3 domain of the

MHC class I molecule, the hinge region would need to adopt an extended

structure since the Ig-like domain is only approximately 35Â (Zamoyska, 1994).

The hinge region of C D B a is 45 amino acids long and is highly 0-glycosylated

and contains numerous proline residues. These features are characteristic of extended structures, helping to stabilise the extended conformation and protect

from proteolysis. An extended hinge region would allow C D Ba to bind to the

is also extended since it has recently been shown to interact with MHC class I

via its external Ig-like domain (Wheeler et ai, 1998), although the precise

residues of MHC contacted are not yet known.

The binding sites of CD4 and CDBa on the MHC molecule is separate

from the peptide binding domain contacted by the IC R . This implies a single

MHC molecule can be bound by both the TCR and C D 4 or CDB coreceptor,

potentially increasing the overall avidity of the interaction. There are indications that, although the CDB heterodimer and homodimer have similar affinity for MHC, the heterodimer has a more significant effect in influencing the binding of

the TCR to MHC (Garcia e ta i, 1996; Renard e ta i, 1996). The two N-terminal

domains of CD4 contact the MHC class II molecule, while the two membrane

proximal domains of CD4 have been shown to contact the TCR (Saizawa et ai,

19B7). No such interaction with the TCR/CD3 complex has been reported for

CDB, although it has been suggested that CDBp may be able to interact with

the TCR without MHC involvement (Kwan Lim et a i, 199B; Wheeler et ai,

199B), which may account for the enhanced binding of the TCR to MHC in the

presence of the C D B ap heterodimer. If this is true, the hinge region of CDBp

would be the most likely region to be mediating this interaction since the Ig-like

domain has been shown to bind with the MHC molecule (Wheeler et ai, 199B).

The cytoplasmic domains of CD4 and CDBa associate with the protein

tyrosine kinase p5 6'ck (ick) through a common CXCP motif (Shaw e ta i, 1990).

The cytoplasmic domain of CDBp does not contain this motif and has been

shown not to interact with Ick (Zamoyska e ta i, 19B9), although it can regulate

and enhance the CDBa-associated Ick kinase activity (Yoko I he e ta i, 199B).

Antibody cross-linking of the TCR with either CD4 or CDB leads to Ick-mediated

tyrosine phosphorylation of intracellular substrates (Gilliland et ai, 1991),

including the ITAMs of the TCR^ chain (Veillette et ai, 19BB), and enhanced

al., 1989). This suggests that CD4 and CDB can potentiate the activation signals delivered through the TCR, by physically associating with the same MHC ligand as the TCR potentially increasing the avidity of the interaction, and bringing Ick in the complex allowing signal transduction.