CD4 on the Road to Coreceptor Status

The advent of monoclonal antibody technology in the late 1970s initiated a wave of discovery that lead to the identification of many important cell surface proteins that defined unique cellular populations with restricted functions (1). In the early 1980s, antibodies to T4 (now known as CD4) and T8 (now known as CD8) were shown to identify unique subpopulations of T cells with either helper or cytotoxic activity, respectively (2–6). Importantly, antibodies to CD4 (T4/Leu3 in humans; L3T4 in mice) were shown to block the MHC class II-mediated proliferation and function of T cells leading to the suggestion that CD4 was intimately involved in the cooperative recognition of MHC class II associated foreign antigen by T cells (5,7,8). Early studies by the Marrack/Kappler and Burakoff labs had suggested that CD4 binding to MHC class II molecules might increase the overall avidity between T cells and APCs (9–11). However, direct evidence for such an interaction had remained frustratingly elusive and it wasn’t clear if additional molecules were required for this interaction. Furthermore, the function of this interaction was controversial.