CD4 is a co-receptor in the cellular immune response, It increases the
avidity of association between a T cell and an antigen-presenting cel
l by interacting with non-polymorphic portions of the complex between
class II major histocompatibility complex (MHC) and T-cell receptor (T
CR) molecules, and it contributes directly to signal transduction thro
ugh its cytoplasmic association with the lymphocyte kinase Lck (ref. 1
). CD4 also serves as the high-affinity receptor for cellular attachme
nt and entry of the human immunodeficiency virus (HIV)(2). The extrace
llular portion of CD4 comprises four immunoglobulin-like domains (D1-D
4), This part of human CD4 (residues 1-369) has been characterized as
a recombinant soluble protein (sCD4)(3,4), and crystal structures have
been described for the human D1D2 fragment(5,6) and for the rat D3D4
fragment(7). We have now determined the structures of intact sCD4 in t
hree crystal lattices. These structures have a hinge-like variability
at the D1D2 to D3D4 junction that might be important in immune recogni
tion and HIV fusion, and a common dimeric association through D4 domai
ns. Dynamic light scattering measurements and chemical crosslinking of
sCD4 corroborate dimerization at high protein concentration. We sugge
st that such dimers may have relevance as mediators of signal transduc
tion in T cells.