Structure of murine CTLA-4 and its role in modulating T cell responsiveness

The effective regulation of T cell responses is dependent on opposing signa ls transmitted through two related cell-surface receptors, CD28 and cytotox ic T Lymphocyte-associated antigen 4 (CTLA-4). Dimerization of CTLA-4 is re quired for the formation of high-avidity complexes with B7 ligands and for transmission of signals that attenuate T cell activation. We determined the crystal structure of the extracellular portion of CTLA-4 to 2.0 angstrom r esolution. CTLA-4 belongs to the immunoglobulin superfamily and displays a strand topology similar to Vor domains, with an unusual mode of dimerizatio n that places the B7 binding sites distal to the dimerization interface. Th is organization allows each CTLA-4 dimer to bind two bivalent B7 molecules and suggests that a periodic arrangement of these components within the imm unological synapse may contribute to the regulation of T cell responsivenes s.