The transcriptional coactivator OCA-B re-wires metabolism and promotes CD4 T cell memory

Abstract

Abstract OCA-B (Pou2af1/OBF-1/Bob.1) is a transcriptional coregulatory protein that is not expressed in naïve CD4+ T cells, but becomes stably induced following antigen exposure and T cell activation. We have previously shown that the transcription factor OCA-B interacts with, Oct1 (Pou2f1) is a potent regulator of metabolism. Oct1 dampens oxidative metabolism of amino acids in mitochondria and counteracts reactive oxygen species production. Possible roles of OCA-B in metabolism have not been tested. Our prior work also indicates that both OCA-B and Oct1 are critical for the generation of functional CD4 memory T cells in response to pathogen infection. By co-transferring SMARTA TCR transgenic T cells ectopically expressing OCA-B and empty vector controls into recipient mice, and infecting the recipients with LCMV, we show that OCA-B does not affect primary effector responses, but is sufficient to promote formation of long-lived memory T cells. Although there are no differences in T cell numbers or function at peak response, changes in the expression of proteins such as CD62L and ICOS are consistent with preferential entry into the memory pool and stronger response upon rechallenge. Transcriptomic profiling of cells at the same peak pathogen response timepoint identifies ~80 genes significantly differentially expressed by ectopic OCA-B expression. These genes encode metabolic regulators and transcription master regulators indicative of metabolic rewiring of these cells. This prediction was confirmed by profiling glycolytic and oxidative metabolism in OCA-B conditional knockout and control naïve CD4 T cells stimulated and rested in vitro. These results indicate that expressing OCA-B may be useful as a method of enhancing CD4 memory.