Thursday, November 21, 2024
11/21/2024
CD8+ T lymphocytes are essential players in mounting protective cellular immune responses against pathogens and malignantly transformed cells. To sustain immunocompetency, the naïve CD8+ T cell pool must be maintained at a stable size. Upon activation, naïve CD8+ T cells differentiate into cytotoxic effector and memory cells that clear pathogens and provide heightened long-term protection, respectively. With the advent of demonstrated efficacy of adoptive cell therapy using naturally occurring or gene-engineered T cells, it is critical to improve our understanding of the molecular mechanisms underlying CD8+ T cell homeostasis, fate decision and differentiation. Such knowledge has important bearing on rational design of prophylactic vaccines and immunotherapy to treat viral infections and cancers. Transcriptional and epigenetic regulation represents an important research front in CD8+ T cell biology. A plethora of factors have been extensively investigated for their capacity of controlling CD8+ T cell activity. It remains a major knowledge gap on how the actions of the CD8+ regulatory factors are orchestrated within the framework of three-dimensional (3D) genome organization. Our research goal is to uncover the less-charted regulatory functions of chromatin architecture in programming CD8+ T cell homeostasis and differentiation. The specific aims are as follows: Aim 1. To investigate Tcf1/Lef1 cooperativity with CTCF and Stat5 to promote CD8+ homoeostasis. Homeostatic cytokines (IL-7 and IL-15) and Stat5 pathway have an established central role in maintaining CD8+ T cell pool size. We will use unbiased systems biology approaches to determine the interplay of Tcf1/Lef1, CTCF and Stat5 on the levels of genomic elements and 3D genomic topology. These studies will place the dogmatic Stat5 pathway within the framework of 3D genome organized by Tcf1/Lef1 and CTCF, providing architectural basis for regulation of CD8+ homeostasis. Aim 2. To investigate the requirements for CTCF in CD8+ T cell-mediated anti-viral/tumor immunity. Memory CD8+ T cells, especially the CD62L+ central memory T (Tcm) cells, provide heightened protection against the same pathogen. We will combine high-resolution HiChIP and state-of-the-art functional assays to establish the causative link between CTCF-anchored chromatin interactions and CD8+ T cell functional output. Using inducible expression of chimeric antigen receptor (CAR) in naïve CD8+ and Tcm cells, we will further discern the intrinsic requirements for CTCF in differentiation of tumor-infiltrating CAR-T cells. This proposal will mechanistically elucidate the dynamic interplay of genome organizers and chromatin architecture in programming CD8+ T cell homeostasis and differentiation in anti-viral and anti-tumor immunity. These efforts may lead to paradigm-shifting advances in scientific knowledge, and provide novel insights into devising more effective vaccines and therapeutics for infectious diseases and cancers.
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