Our Projects
Immune-microbe environmental alteration leading to transgenerational epigenetic inheritance of skin barrier phenotypes
The host-microbiota relationship has evolved to shape mammalian physiology, including immunity, metabolism, and development. Germ-free models are widely used to study microbial effects on host processes such as immunity. Upon investigating germ-free skin phenotypes, we found that both germ-free and T cell-deficient mice exhibit a robust sebum secretion defect persisting across multiple generations despite microbial colonization and T cell repletion. These phenotypes are inherited by progeny conceived during in vitro fertilization using germ-free sperm and eggs, demonstrating that non-genetic information in the gametes is required for microbial-dependent phenotypic transmission. Accordingly, gene expression in early embryos derived from gametes from germ-free or T-cell deficient mice are strikingly and similarly altered. These findings demonstrate that microbial and immune-dependent regulation of non-genetic information in the gametes can transmit inherited phenotypes transgenerationally in mice. This mechanism could rapidly generate phenotypic diversity to enhance host adaptation to environmental perturbations. Ongoing projects related to this topic include: investigating immune mechanisms of heritability, surveying the effects of altered immune-microbe environment on immune function of progeny, dissecting epigenetic factors responsible for responding to immune-microbial cues, among others.
Immune-mediated control of sebum secretion by the skin
We have recently discovered that T cells that are stimulated by a keratinocyte-derived cytokine TSLP induces sebum secretion from sebaceous glands of the skin. Sebum is a high calorie lipid-rich substance that provides barrier protection to the skin. When this sebum secretion system is put into high gear, we found that high fat diet-fed mice selectively lose adipose tissue and lower their tissue triglyceride levels, providing benefit to obesity-related disorders. At homeostasis, we believe that the T cell/TSLP/sebum axis is important for providing skin barrier function in response to pathogens and commensals. Ongoing projects involve the investigation of the mechanism by which TSLP-stimulated T cells promote sebum secretion and how this axis interacts with skin commensals and pathogens.
DGK as a novel checkpoint target for reactivation of exhausted T cells
Diacylglycerol (DAG) is an important second messenger downstream of T cell activation through their T cell receptor (TCR). DAG is negatively regulated by a kinase called DAG kinase (DGK), which phosphorylates DAG into phosphatidic acid, thereby terminating DAG-mediated signaling. Our previous work has shown that DGK deficiency leads to heightened NK cell and T cell activation and resistance to PD-1-mediated inhibition. Ongoing projects in the lab involve the investigation of how DGK and its downstream pathways (such as ERK) affect T cell responses during chronic viral infection with LCMV clone 13.
Developing a mouse model of Idiopathic Multicentric Castleman Disease (iMCD)
iMCD is a rare but life-threatening cytokine storm disorder of unknown etiology. To understand more about iMCD pathogenesis, we have been studying the signaling pathways and transcriptomics in cells from iMCD patients. Through this work, we have identified a number of key signaling molecules that might be important in iMCD pathogenesis including mTOR and IFN signaling. We are currently developing mouse models of iMCD to mechanistically test the role of these pathways in this devastating disease.