This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Appropriate T cell differentiation is a critical component of a normal immune response and insures sufficient immunity to a variety of insults, including microbial pathogens. During T cell differentiation, the cytokine loci undergo significant changes in chromatin structure that facilitate coordinated expression of the cytokine genes. We recently found that altered histone acetylation, coupled with cytokine gene transcription, occur within hours of T cell stimulation. Interestingly, the patterns of transcription and chromatin remodeling were independent of Th1/Th2 polarization. The early changes in histone modifications at the promoters of the cytokine loci were plasic and could be maintained or reversed depending on the cytokine environment that the T cells encountered subsequently. The goal of this proposal is to examine early cytokine transcription as well as changes in the local chromatin environment around the cytokine loci to determine whether these early changes set the stage for subsequent effector differentiation and thus may be an important determinant of cell fate. The scientific aims of this proposal are to study the regulation of early transcription of T helper cytokines in uncommitted T cells. We hypothesize that this early transcription is a critical step in determining the ultimate differentiated state of the effector cells. We will assess the role of chromatin remodeling within the cytokine loci on this early transcription and compare these events to those in differentiated effector cells. Inappropriate T cell differentiation has been implicated in a number of pathological states and is a critical determinant of immune responsiveness.
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