Stat6 activation and Th2 cell differentiation [correction of proliferation] driven by CD28 [correction of CD28...

CD28 engagement by specific monoclonal antibody (mAb) or binding of the natural ligands, CD80 and CD86, induces tyrosine phosphorylation of CD28, which in turn recruits and activates the signal transducer and activator of transcription 6 (Stat6). The Stat6 association with CD28 is specifically induced by CD80 or CD86 ligand binding and is not dependent upon the secretion of IL-4 or IL-13. Activated Stat6 translocates to the nucleus and binds to a Stat6-responsive element on the human IL-4 promoter. CD28 ligation induces Stat6-dependent transcriptional activation of a reporter gene under the control of a multimerized Stat6-responsive element fused to an essential part of the IL-4 promoter. Primary stimulation of naive CD4(+) T cells with anti-CD28 mAb in the presence of IL-2, but in the absence of anti-CD3 mAb induces preferential production of IL-4 and expression of CCR4 mRNA after secondary stimulation with anti-CD3, indicating the preferential differentiation of Th2 cells. These findings suggest that initial IL-4 production required for commitment of naive T cells toward Th2 cells may be provided in response to signals delivered via CD28 by antigen-presenting cells.