Defining Distinct Mechanisms of Interferon Gamma Trained Immunity

About This Grant

Project Summary / Abstract Trained immunity, which refers to the ability of innate immune cells to retain memory of prior stimuli, has been well documented in the past decade. Interferon gamma (IFNγ), a cytokine secreted by T-cells in response to infection, has been identified as a primary driver of trained immune phenotypes across a variety of model systems. IFNγ induces significant transcriptional changes across several innate immune cell types such as monocytes and mature macrophages present in the tissue. However, the individual contributions of these cell types to innate immune memory remains unidentified. For example, IFNγ can polarize tissue-resident macrophages and induce long-term epigenetic, metabolic, and signaling changes. Additionally, IFNγ can skew the differentiation of monocytes towards a pro-inflammatory macrophage phenotype distinct from IFNγ- polarized macrophages. This is to say that mature cells present in an inflamed tissue prior to the start of an infection respond differently and retain memory differently than undifferentiated monocytes entering the tissue upon inflammation This proposal posits that IFNγ induces memory through distinct mechanisms in mature innate immune cells such as macrophages versus maturing cells such as monocytes. The hypothesis is that mature cells undergo acute polarization and short-lived reversible memory, while differentiating monocytes are permanently reprogramed towards a distinct mature cell type. Aim 1 will explore how IFNγ transcriptionally and functionally redirects mature and immature monocytes/macrophages in vitro and in vivo. Aim 2 investigates the mechanism through which immature monocytes may be reprogrammed by IFNγ by first examining the epigenetic changes induced by IFNγ during differentiation and probing whether these changes are reversible and then by identifying novel genes or signaling pathways that may drive this differentiation. This mentored career development award will support the training of Dr. Aleksandr Gorin, and infectious disease physician-scientist at UCLA to support his transition to an independent investigator. Dr. Gorin is mentored by an accomplished group of immunologists headed by Dr. Alexander Hoffmann, a leading systems immunologist and expert in the field of innate immune signaling. The proposed scientific plan will allow Dr. Gorin to achieve his specific training aims of (1) becoming proficient in a broad range of functional profiling of human innate immune cells, (2) obtaining further training in advanced bioinformatics and single-cell analyses, and (3) learning the statistical skills necessary to analyze large clinical datasets.