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.