Signalling through the T cell costimulatory receptor CD28

grantor: University of TorontoT cells are important regulators of the adaptive immune response. T cells become activated when they interact with specialised antigen presenting cells that express processed peptides from pathogens. CD28 is a costimulatory cell surface receptor expressed by T cells. In concert with the T cell receptor for antigen (TcR), CD28 generates signals that promote cytokine production and cell proliferation. T cells that recognise antigens on self tissues that do not express the CD28-ligands, B7-1 or B7-2, enter a non-responsive state, termed anergy, or may undergo programmed cell death. As such, CD28 plays a critical role maintaining immunological tolerance against self-antigens, while promoting immune responses against invading organisms. I have investigated how CD28 transmits signals inside T cells. One consequence of the interaction between B7 and CD28 is that the cytoplasmic domain of CD28 becomes phosphorylated on a tyrosine residue that serves as a docking site for the SH2 domains of phosphoinositide 3-kinase (PI3K) and Grb2. A number of studies have suggested that it is through these interactions that CD28 provides costimulatory signals. I have used a genetic approach to identify the role of this SH2-binding site for costimulation 'in vivo', and found it not to be essential for costimulation of proliferative responses and IL-2 production. Therefore, CD28 must use other protein-interaction sites to recruit intracellular signalling proteins. I have characterised two proline-rich regions in CD28 that bind SH3 domains. One of these regions binds the SH3 domains of Grb2. The recruitment of Grb2 to CD28 through the SH3 domains leaves the Grb2 SH2 domain free to bind signalling proteins that are phosphorylated on tyrosine. This allows CD28 to connect with other signalling molecules, such as Shc, that are involved in T cell activation. The other proline-rich region of CD28 binds the SH3 domain of the tyrosine kinase Itk. CD28 thus brings Itk in proximity with potential proteins involved in CD28 costimulation. The binding of the cytoplasmic domain of CD28 to the SH3 domain of Itk increases the tyrosine kinase activity of Itk.Ph.D