Role of CD4 dimerization in T cell activation

Key to development of immunotherapies and vaccines is a thorough understanding of the complex pathways that govern T cell activation. On helper T lymphocytes, the CD4 molecule is a critical player in the early stages of activation, serving to enhance recognition of MHC-peptide complexes by the TcR and to facilitate efficient p56lck recruitment in the vicinity of the engaged TcR:CD3 signalling module. Originally, the CD4 molecule was believed to exist as a monomer on the cell surface; however, within the last years, a growing body of crystallographic, computer modeling and functional studies has suggested that CD4 might assume a dimeric/oligomeric state.Here, we provide direct experimental evidence for the existence of CD4 dimers on the surface of transfected cells from haematopoietic and fibroblastic origin, as well as in primary T lymphocytes. Furthermore, we accurately map the dimerization site at residues K318 and Q344 within the fourth extracellular domain of CD4. More importantly, we demonstrate that dimer formation is essential for the coligand and coreceptor functions of CD4 in T cell activation. Specifically, we show that CD4 dimerization is required for efficient IL-2 production, yet appears without effect on early TcR-associated signalling. Using FRET video microscopy to visualize the dynamics of CD4 molecules during T cell activation, we reveal that CD4 dimers only promote immunological synapse formation, then further accumulate within the synapse.Overall, the study presented in this thesis sheds light on the refined molecular interplay of the various surface receptors and signalling modules that dictates the efficiency of the T lymphocyte antigenic response