Immunological memory provides critical protection against pathogens and can drive autoimmune and anti- tumor responses, but our understanding of the underlying molecular mechanisms is inadequate. The transcriptional co-regulator OCA-B (also known as Bob.1, OBF-1 and Pou2af1) is induced in stimulated primary CD4 T cells, where it docks with its cognate transcription factor Oct1 to regulate critical targets ? among them Il2, Il21, Ifng, Icos, Ctla4, Csf2 (Gmscf), Tnfrsf4 (Ox40), Tbx21 (Tbet), and Stat5a. OCA-B?s effects do not manifest upon simple stimulation of CD4 T cells. Instead, withdrawing the stimulus, then resting and re-stimulating OCA-B deficient cells results in gene expression defects of 100-fold or more. OCA-B mediates these effects by recruiting the Jmjd1a histone lysine demethylase to remove inhibitory histone H3K9me2 chromatin modifications at silent but previously activated target loci. In vivo, both OCA-B and Oct1 are dispensable for T cell development and primary CD4 response but required for CD4 memory formation and response to re-challenge1. This published foundational work leads to many unanswered questions: Can OCA-B be used to prospectively identify CD4 memory cells? Can it directly drive memory? What is its role in CD8 cells? In autoimmunity? In anti-tumor immunity? Why are OCA-B target genes frequently adjacent to one another as linked gene pairs? Can OCA-B be targeted pharmacologically? Our proposal addresses these questions. The overarching hypothesis is that in both CD4 and CD8 T cells, OCA-B coordinately regulates the expression of genes encoding cytokines and other immunomodulatory proteins to control pathogen response and memory cell formation.
Aim 1 : Determine if Jmjd1a recruitment by myristoylated OCA-B promotes CD4 memory.
Aim 2 : Determine the role of OCA-B in chronic infection.
Aim 3 : Determine if myristoylated OCA-B facilitates interactions between distant loci.
Relevance: The project focuses on mechanisms by which OCA-B governs the development of anamnestic responses in T cells, is therefore most relevant to vaccine development, infectious and autoimmune disease, and anti-tumor response. Therefore, the findings from experiments in the proposal will advance the field significantly and have significant public health relevance.
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