Somatic Plasticity for Discriminating Self from Non-Self
How does the immune system distinguish friend from 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 Noise & Cell Plasticity
Chromatin is the template that records and transmits epigenetic information by integrating intrinsic (e.g. chromatin remodeling) and extrinsic (e.g. metabolism) activities to specify cell fate. The biomolecular interactions underlying these activities are inherently noisy, causing cells to randomly deviate from their established states. The Koh Lab strives to uncover the mechanisms that suppress or augment fluctuations in chromatin states to maintain stability or promote plasticity of somatic cells. We develop technology that interrogates at single-cell resolution how somatic plasticity is programmed during development and exploited in pathogenesis.