Innate and innate-like lymphocytes are recently appreciated tissue-resident immune cells with vital roles in the initiation of tissue inflammatory responses. As early responders during tissue perturbation, these cells are integral in shaping both protective and pathologic immune responses, as well as contributing during normal tissue development and remodeling. We are particularly focused on innate lymphocytes that are associated with type 2/allergic immune responses. Through understanding the local signals and micro-environments that regulate innate type 2 immune responses, we hope to manipulate these pathways to both limit allergic pathology (asthma, allergy, atopic dermatitis) and promote beneficial allergic responses in settings of chronic, low-grade inflammatory diseases (cardiovascular disease, obesity/diabetes,) where we and others have found type 2 immunity to be protective. Our group is using a multifaceted approach focused on in vivo mouse models, including cytokine reporter/deleter mice, advanced imaging with tissue clearing, flow immunophenotyping, genomics, and pathologic challenges to study these questions.
One area of laboratory focus is to understand the tissue 'niche" which supports and regulates resident lymphocytes, including both ILC2 and Treg. We have identified specific micro-anatomic sites where ILC2 and tissue Treg reside, and are currently using a combination of advanced imaging, genetics, and molecular approaches to characterize these sites of immune-tissue cross-talk. We are particularly interested in the regulation and sources of the IL-1 family member IL-33, a dominant positive regulator of tissue ILC2 and Treg. We hope that these studies will lead to a better understanding of how tissue-resident lymphocytes coordinate immune responses from their discrete micro-anatomical niches to impact the physiology of their host tissue, and how these interactions go awry during pathologic states.
A second area of laboratory focus is to understand the immune contributions during obesity and type 2 diabetes. Obesity promotes local inflammation in visceral adipose tissue that sustains systemic inflammation, insulin resistance, and the development of type 2 diabetes. However, the function and regulation of normal immune cells in healthy adipose tissue is poorly understood. We have found that allergic, type 2 immune cells are surprisingly abundant in healthy, lean adipose tissue and are co-regulated to maintain metabolic health and limit obesity induced inflammation and insulin resistance. These findings suggest allergic immunity, traditionally associated with pathology (asthma, atopy, allergy) as well as protection from multicellular helminthic worms, also plays a central role in the normal physiologic regulation of metabolism, and may participate more broadly in tissue homeostasis and repair. We are studying the allergic immune module in adipose tissue during conditions of metabolic health, obesity, and post infection with helminths, bacteria, or viruses. We are focused on the regulation, interactions, cytokine production, and metabolic impact of the cells in this allergic module, including group 2 innate lymphoid cells (ILC2), eosinophils, alternatively activated macrophages (AAM, M2), and tissue regulatory T (Treg) cells. We anticipate this knowledge will accelerate the development of human therapeutics that can restore balanced anti-inflammatory, allergic-type immune responses that decline in adipose tissue with obesity and old age, limiting the progression of insulin resistance and type 2 diabetes.
A third area of laboratory focus is at the interface of neuroimmunology. Although microglia, the brain-resident macrophages, are known to impact normal neuronal circuit development, as well as shaping beneficial and pathologic responses during neurodevelopmental and neurodegenerative disorders, the role of brain-resident lymphocytes is largely unknown. In collaboration with the AV Molofsky lab, we are studying the regulation and function of brain-resident meningeal lymphocytes, including how these lymphocytes impact glia to shape developing neuronal circuits.