OUR RESEARCH GOALS
Our laboratory studies cells of the immune system called innate lymphoid cells (ILCs). ILCs consist of a diverse family of tissue-resident and circulating cells that produce protective proinflammatory and regulatory cytokines in response to infection, commensal bacteria, or locally-produced cytokines. During chronic inflammation, however, persistent inflammatory signals can lead to unrestrained activation of ILCs, exacerbating colitis, dermatitis, tumorigenesis, and metabolic dysfunction. Our long-term research goals are to understand the cellular and molecular signals that direct the protective versus pathologic function of tissue-resident and circulating ILCs. Understanding these processes has broad implications for the treatment of type 2 diabetes, cancer, and infectious diseases.
Obesity-associated insulin resistance
Obesity has become an alarming epidemic and is a source of chronic inflammation that is associated with the enhanced risk of developing cardiovascular disease, type 2 diabetes (T2D), and certain types of cancer. Recent evidence from mouse models of diet-induced obesity (DIO) suggest that the immune system potentiates obesity-associated chronic inflammation to drive insulin resistance (which can lead to type 2 diabetes). However, the signals that activate the immune system during obesity remain unclear.
Our laboratory recently discovered a unique population of adipose-tissue resident innate lymphocytes (called ILC1) that produce large amounts of the proinflammatory cytokine interferon (IFN)-gamma shortly following DIO. We found that early production of the cytokine interleukin (IL)-12 lead to rapid production of IFN-gamma by ILC1 to potentiate local adipose tissue inflammation and contribute to DIO-associated insulin resistance.
Our current projects aim to further characterize the early cellular sources of inflammation in the adipose tissue during DIO, and determine the molecular mechanisms that promote the activation of the innate immune system during obesity. The implications of these findings can potentially have profound effects on the treatment of obesity-associated diseases.
Cancer immunosurveillance and immunoediting
Natural Killer (NK) cells, the first identified member of ILCs, constantly patrol host tissues against transformed cells in a process known as cancer immunosurveillance. Our past work has shown that NK cells protect against cancer formation by sculpting the immunogenicity of developing tumors in a process known as cancer immunoediting. This process involves elimination of highly immunogenic “unedited” tumor cells followed by the eventual escape of less immunogenic, “edited” cells. While we have shown previously that “unedited” tumor-derived cytokines have been implicated in contributing to NK-cell mediated tumor rejection by enhancing their recruitment to the tumor microenvironment, the “edited” tumor-expressed genes that contribute to immune escape during tumor progression remain poorly understood. Therefore, we have identified a novel “edited” tumor gene signature and aim to functionally validate these gene candidates by using an unbiased genome-wide CRISPR-Cas9 screen in vivo.
Identification and validation of novel tumor-intrinsic immune evasion mechanisms may improve current immunotherapies or offer improved treatments for patients that do not respond to immunotherapy.
ILC memory formation and survival
The innate immune system was previously considered to be composed of short-lived cells that perform effector functions during infection and then rapidly die once their task is accomplished. However, our studies and others suggest that ILCs posses characteristics of the adaptive immune system, such as clonal expansion, longevity, and immunological memory.
We have recently demonstrated that virus-specific NK cells persist to form memory cells by removing damaged mitochondria through a process known as mitophagy (which involves the induction of autophagy to remove mitochondria). Our group also demonstrated that autophagy is required for the survival of lymphocytes following periods of proliferation. Current projects are aimed at understanding the molecular mechanisms that control the induction of autophagy and mitophagy in lymphocytes during viral infection, and to further understand the cell fate decisions that dictate memory cell formation and survival. Understanding these fundamental processes could have implications for future vaccine design.