Ectopic Gene Expression in Thymic Epithelia that Imposes Immune Tolerance
How does the immune system distinguish friend vs. foe? The thymus gives rise to T cells that harbor specificities to virtually any pathogen; however, this stochastic process also generates specificities for self. To purge self-reactive clones from the repertoire, epithelial cells of the thymic medulla express nearly the entire coding genome to mirror the peripheral ‘self’ and display tissue-specific antigens (e.g. insulin) to prevent autoimmunity (e.g. diabetes). The Koh Lab strives to identify the determinants and developmental cues that program this somatic plasticity, to leverage the mechanisms for cancer immunotherapy and treatment of autoimmune diseases.
Acquisition of T Cell Effector Plasticity and Leukemogenesis
T cells can elicit one of many distinct functions (e.g. kill, induce differential cytokine milieu, repress activation, tissue repair, metabolic homeostasis, etc.) and redirect their initial response to an alternate fate depending on the nature of the pathogen and environment. This T cell plasticity is central to protective immunity and its dysregulation contributes to oncogenesis. How can T cells respond in so many different ways? How does this cellular plasticity leave it vulnerable for leukemic transformation? The Koh Lab strives to elucidate the underlying epigenetic circuit to avail new therapeutic avenues for leukemia, vaccine efficacy and cancer immunotherapy.
Chromatin: Highly Plastic Template with Memory Faculty for Specifying Cellular States
Tissues develop from specialized differentiation of cells that originate from a single zygote. Aristotle described this developmental process as ‘epigenesis’. Chromatin is the template that records and transmits epigenetic information by integrating the actions of transcription factors, signal transduction, and metabolic pathways to specify cell fate. The Koh Lab develops technology that interrogates the state and conformations of chromatin and corresponding gene network dynamics at single-cell resolution to understand how somatic plasticity is programmed during development and exploited during tumorigenesis.