A point mutation in CD28 distinguishes proliferative signals from survivalsignals

Upon interaction with its ligand, B7, CD28 becomes phosphorylated on tyrosi nes, One tyrosine in particular (Y-170 in mouse CD28, Y-173 in human CD28) has received much attention. This is because it permits CD28 to recruit SH2 -containing signaling molecules, including phosphoinositide 3 kinase, Grb2 and Gads. Using mice we employed a transgenic approach to express a tyrosin e-->phenylalanine mutant form of CD28 that uncouples these SH2-mediated int eractions from CD28. The CD28 mutant is unable to up-regulate expression of the prosurvival protein Bcl-x(L), rendering the T cells move susceptible t o radiation-induced death. Nonetheless, this mutated form of CD28 still pre vents the induction of anergy and promotes T cell proliferation, interleuki n 2 secretion and B cell help. Thus, we describe a single point mutation wi thin the CD28 cytoplasmic domain that uncouples signals required for prolif eration and survival.