Daa. Vignali et al., THE 2 MEMBRANE PROXIMAL DOMAINS OF CD4 INTERACT WITH THE T-CELL RECEPTOR, The Journal of experimental medicine, 183(5), 1996, pp. 2097-2107
During T cell activation, CD4 is intimately involved in colocalizing t
he T cell receptor (TCR) with its specific peptide ligand bound to cla
ss II molecules of the major histocompatibility complex (MHC). Previou
sly, the COOH-terminal residues, Trp62/63, which flank the immunodomin
ant epitope of hen egg lysozyme (HEL 52-61), were shown to have a prof
ound effect on TCR recognition. CD4 maintains the fidelity of this int
eraction when short peptides are used. To determine which portion of C
D4 was responsible for this effect, a series of CD4 mutants were made
and transfected into CD4 loss variants of two HEL 52-61-specific T cel
l hybridomas. Surprisingly, some CD4 mutants that failed to interact w
ith MHC class II molecules (D2 domain mutant) or with p56(lck) (cytopl
asmic-tailless mutant) restored responsiveness. Nevertheless, a signif
icant reduction in association between cytoplasmic-tailless CD4 and th
e TCR, as determined by fluorescence resonance energy transfer, was ob
served. Thus, neither colocalization of CD4 and the TCR nor signal tra
nsduction via CD4 was solely responsible for the functional restoratio
n of these T cell hybridomas by wild-type CD4. However, substitution o
f the two membrane proximal domains of murine CD4 (D3 and D4) with dom
ains from human CD4 or intercellular adhesion molecule 1 not only abro
gated its ability to restore function, but also substantially reduced
its ability to associate with the TCR. Furthermore, the mouse/human CD
4 chimera had a potent dominant negative effect on T cell function in
the presence of equimolar concentrations of wild-type CD4. These data
suggest that the D3/D4 domains of CD4 may interact directly or indirec
tly with the TCR-CD3 complex and influence the signal transduction pro
cesses. Given the striking structural differences between CD4 and CD8
in this region, these data define a novel and unique function for CD4.