Using site-directed mutagenesis informed by high-resolution CD4 structural data, we have investigated the role of residues of the C'C" ridge region of human CD4 on class H major histocompatibility complex (MHC) binding. This (17,18) results in diminished CD4+ T-cell development and impairment of B-cell functions. In mature T lymphocytes, CD4 crosslinking is known to provide a costimulatory signal during T-cell activation via the T-cell receptor (TCR) (19,20). The signaling functions of CD4 are believed to be mediated by p56lck, a member ofthe src protein tyrosine kinase family, which is noncovalently associated with the cytoplasmic domain of CD4 (21, 22). Colocalization of the TCR and CD4 on the surface of stimulated T lymphocytes may facilitate the activation process by bringing the CD4-associated kinase into proximity with the TCR signaling machinery (23,24).CD4 is a member of the immunoglobulin (Ig) superfamily. It has a large extracellular portion (residues 1-372), a transmembrane segment (373-393), and an intracellular "tail" (394-433) (25). The extracellular part consists of four Ig variable (V)-like domains. The structure of the two N-terminal domains has been determined to 2.2 A by x-ray crystallography (26, 27). The first and second domains are antiparallel (-barrels with the characteristic Ig connectivity. They are joined by a continuous 13-strand connector, giving the molecule a rod-like structure. The first domain closely resembles a VK chain. There are nine (3-strands, with strands A, C, C', C", F, and G forming one surface and strands B, D, and E forming the other. The C'C"-loop ofCD4 domain 1 is larger than the corresponding loop in an Ig V domain. As a result, it protrudes noticeably from the molecular surface (26).Previous homology-scanning mutations indicated that the interaction of CD4 with class II

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