EID Faculty

B.S., Biology, Visual Arts, Duke University
Ph.D., Immunology, Stanford University School of Medicine
Postdoctoral Training, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH

RESEARCH INTERESTS
The major emphasis of my laboratory is to elucidate how aberrations in lymphocyte signaling contribute to deranged immune homeostasis in novel lymphoproliferative disorders and primary immunodeficiencies. Our research focuses on identifying novel molecular regulators of lymphocyte apoptosis and differentiation in humans, with the ultimate goal of informing new therapeutic approaches for controlling immune responses by manipulating cell death sensitivity.

ONGOING PROJECTS

1. Signal regulation and physiological relevance of specific T cell apoptosis pathways

The regulation and eventual contraction of activated T cells during an immune response is critical for maintaining equilibrium in the immune system and preventing unwanted damage to host tissues. Normally, specific apoptosis programs induced by T cell receptor (TCR) restimulation or cytokine withdrawal work to cull the majority of activated effector T cells, leaving a small pool of memory T cells behind to protect against subsequent infections (Fig 1). We now appreciate that genetic defects in lymphocyte apoptosis directly contribute to excess lymphoproliferation in humans. For example, T cells from patients with X-linked lymphoproliferative disease (XLP-1) display a profound defect in T cell receptor restimulation-induced cell death (RICD; also known as activation-induced cell death), a critical self-regulatory apoptosis program that constrains effector T cell expansion. Our lab has defined several biochemical mechanisms by which signaling lymphocyte activation molecule (SLAM)-associated protein (SAP), which is lost or mutated in XLP patients, facilitates RICD. Most recently, we led an international collaborative effort demonstrating that inhibition of diacylglycerol kinase alpha (DGKa), a modulatory enzyme with elevated activity in SAP-deficient T cells, presents a viable therapeutic approach for treating EBV-induced fulminant mononucleosis in XLP-1 patients, via restoration of RICD. Collectively, this work underscores the physiological relevance of RICD in preventing excessive T cell accumulation, severe immunopathology and mortality in XLP patients infected with EBV. We continue to investigate how RICD sensitivity is “tuned” via SAP-dependent signals.

We are also investigating novel links between metabolic programming and apoptosis sensitivity in human T cells. Our recent work indicates that while excessive anabolic metabolism (i.e. glycolysis) leaves effector T cells more susceptible to RICD, catabolic metabolism (i.e. autophagy) can protect T cells derived from distinct memory compartments from death induced by cytokine withdrawal. We have delineated specific molecular mechanisms responsible for these changes in cell death sensitivity, and continue to investigate how specific metabolic programs affect T cell viability. Our work illuminates how metabolic changes govern T cell survival, and may explain why certain memory T cells give rise to a larger, more robust effector response (via reduced cell death) that better protects the host when challenged with a pathogen or tumor.

2. Novel immunological disorders linked to mutations in CARD11

We discovered that gain-of-function (GOF) mutations in the CARD11 gene cause a rare congenital B cell lymphoproliferative disorder called B cell Expansion with NF-kB and T cell Anergy (BENTA) disease. My laboratory has taken a leading role in the genetic diagnosis and phenotypic characterization of an expanding cohort of BENTA patients (Fig 2). CARD11 encodes a scaffolding protein that links antigen receptor signaling to NF-kB activation in lymphocytes. Unlike the wild-type protein, CARD11 GOF mutants spontaneously oligomerize and drive constitutive activation of NF-kB, contributing to increased proliferation and enhanced survival of both immature and naïve patient B cells. Surprisingly, BENTA patients also exhibit hallmarks of immunodeficiency, including B cell differentiation defects, selective antibody deficiency, and opportunistic viral infections (e.g. molluscum contagiousum, chronic EBV) that reflect impaired T cell responses. Our latest findings pinpoint intrinsic molecular defects in plasma cell differentiation and antibody secretion in activated BENTA patient B cells, despite profound apoptosis resistance that likely explains excessive B cell expansion.

In collaboration with Dr. Joshua Milner (NIH) and others, we are also investigating loss-of-function (LOF) CARD11 mutations in atopic patients with severe eczema. We recently described 4 families with distinct, hypomorphic CARD11 mutations that dominantly interfere with WT CARD11 signaling, resulting in impaired NF-kB and mTORC1 signaling. Extensive structure-function studies of the CARD11 molecule continue in my lab, drawing from an expanding list of natural mutations in human patients. Using cell transfection systems, murine models and primary patient lymphocytes, my lab also continues to investigate how both GOF and LOF CARD11 mutations perturb signaling, differentiation and function of B and T cells.