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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Cellular and Molecular Immunology - A Study Section (CMIA)
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Kelly, Halonna R
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University of Utah
Schools of Medicine
Salt Lake City
United States
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