Research


Elucidating the Basic Principles of Self vs Non-self  Discrimination by the Immune System

Our laboratory investigates the molecular mechanisms of self and non-self discrimination by the immune systems. We are currently focusing on the two topics: (1) the innate immune receptors involved in antiviral immune response, and (2) the transcription factors involved in T cell development of self tolerance.

Antiviral Innate Immunity

Pattern recognition receptors (PRRs) in the innate immune system are responsible for the early detection of pathogen invasion and activation of appropriate immunological responses. We are particularly interested in how a subset of PRRs, such as RIG-I-like receptors, robustly and accurately discriminate between cellular and viral RNAs during infection. It was traditionally thought that the dsRNA structure, which is often present in viral RNAs, provides sufficient means for PRRs to selectively recognize viral RNAs against the background of cellular RNAs. However, accumulating evidence suggests that the mechanism for viral RNA detection is more complex than a simple duplex binding, and the rules that separate self from non-self may not be as rigid as previously thought.

Our mechanistic studies on the RIG-I-like receptors, in particular the discovery of their oligomerization and signaling mechanisms, have provided a new framework for understanding how these receptors detect viral RNAs during infection, how this recognition is coupled to antiviral signal activation, and how certain mutations lead to inappropriate recognition of self RNAs. Our current research focuses on (1) identities of self RNAs that trigger these receptors during pathologic conditions, (2) mechanisms by which these signaling complexes are resolved during the negative regulation of antiviral signaling, and (3) mechanisms of other antiviral RNA binding proteins, such as PKR, ZAP and TRIM25.



 


Transcriptional Regulation of Adaptive Immunity

Unlike the innate immune system, the adaptive immune system establishes its ability to discriminate between self vs. non-self through a series of positive and negative selections of T- and B-cells. In establishing immunological tolerance of T-cells against self antigens, a transcriptional regulator, Aire, plays a central role by up-regulating thousands of peripheral tissue antigens in the thymus medulla, the site of negative selection of self-reactive T-cells. Mutations that impair proper functioning of AIRE result in development of multiorgan autoimmune disease, known as APECED. Aire functions through formation of a large complex with proteins involved in transcriptional control and mRNA processing. However, the precise molecular composition of these complexes, their assembly pathways and the mechanism by which they regulate promiscuous gene expression are poorly understood. Adding to this challenge is a poor biochemical behavior of the Aire protein, which has thus far defied rigorous analyses of its function. We are currently investigating the structural assemblies underlying the apparent aggregation behavior, and how the assembly structure and process play a role in target site recognition and transcriptional regulation.

 



We use a combination of crystallography, electron microscopy, biochemistry and cell biology to dissect molecular principles that govern these molecules in the vertebrate immune system.

Last update: April 2015