Title: Signallinp through the T cell1 costimulatory receptor CD28.

T 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-iigands, 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-anrigens. while promoting immune responses against invading organisms. I have invesrigated 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 i