Perhaps the most fundamental challenge faced by the adaptive immune system is how to distinguish foreign pathogens from normal host stimuli. Our lab is interested in the biochemical and transcriptional strategies employed by lymphocytes to do so; we aim to identify the mechanisms that enable T and B cells to discriminate self from foreign.
(a) Our lab seeks to define the rules and mechanisms that govern B cell responses to specific features of self and foreign antigens, including antigen affinity, valency, biophysical structure, and co-stimulatory signals. We want to understand how self-reactive B cells, despite chronic antigen engagement of the B cell antigen receptor (BCR), are restrained from inappropriate activation and differentiation into antibody-secreting plasma cells. Conversely, we aim to determine how virus-like antigens bypass B cell tolerance. We want to define how this process is disrupted in a variety of autoimmune disease states, and how normal regulatory mechanisms (both biochemical and transcriptional) can be harnessed to restore tolerance on the one hand or optimize vaccine responses on the other.
(b) We are also interested in how developing T cells in the thymus interpret self antigen encounter in order to adopt distinct fates according to the type and intensity of signals received through the T cell antigen receptor (TCR) : deletion, diversion into regulatory lineages, or entry into the mature conventional T cell repertoire. We are also probing how thymocytes adapt and tune their signaling machinery to optimize affinity discrimination and limit inappropriate responses to self.
Our lab takes a range of approaches that span mouse genetics, cellular immunology, signal transduction, and genomics in order to address these questions. In particular, we have characterized and exploited reporter mice (NUR77-eGFP BAC transgenic) in which antigen receptor signaling drives expression of eGFP. This reporter serves as an in vivo sensor of both self and foreign antigen encounter, and serves to unmask enormous clonal heterogeneity among superficially uniform populations of lymphocytes.