Kira Rubtsova, PhD, Instructor
Recently our group has discovered a subset of B cells, called age-associated B cells (ABCs), which appear in elderly female mice and autoimmune prone mice of either gender. We and others have also found ABC-like cells in elderly women suffering from various autoimmune diseases. Our experiments suggest that these B cells can produce autoantibodies and contribute to these diseases. It has been shown that ABCs develop from follicular B cells and their appearance depends on TLR7 signaling. However, the factors involved in the development of ABCs are not known. In this study we explore the lineage defining transcription factors for ABCs. In particular the role of T-bet, a T box transcription factor, is investigated. ABCs express high levels of T-bet and ligation of TLR7 leads to up regulation of this transcription factor in B cells. These data make T-bet a good candidate for a lineage defining transcription factor for ABCs. To find out if this is so, we explored the role of T-bet in the differentiation of B cells. Our data demonstrate that T-bet is necessary and sufficient for the differentiation of B cells into ABCs which indicates that T-bet truly is a lineage transcription factor for these cells. Besides that we were able to identify other factors crucial for the generation of ABCs: interferon gamma (IFNg) and ligation of B cells receptor (BCR). Our results indicate that TLR7, BCR and IFNg signaling synergize in B cells driving high level of T-bet expression. Overall, these findings help to understand the role of T-bet expression in B cells and how changes in T-bet levels with age lead to the perturbations in B cell subsets leading to the age related onset of autoimmune disorders.
Janice White, Research Specialist 1
I am currently studying the repertoire of murine αβ T cells and the bias of T cell receptors for reaction with MHC.
Gina Clayton, Research Specialist 2
My research is focused on structural studies of proteins important in the immune system. I am currently working on the crystallization of a complex consisting of T Cell Receptor (TCR) and its partner, beryllium bound peptide-Major Histocompatibility Complex II (MHC II). This complex is known to activate an immune response to beryllium as part of the chronic lung disease berylliosis in susceptible individuals. Other crystallography goals includes crystallization of non-MHC TCR complexes.
Niyun Jin, MD, PhD, Research Specialist 2
Auto-reactive CD4+ T cells are involved in autogenesis of Type 1 diabetes. In a nonobese diabetic mouse (NOD) model of type I diabetes, we have found a neuropeptide WE14 as an antigen for highly diabetigenic CD4+ T cell clones. WE14 is from posttranslational processing of Chromogranin A. My project is to identify WE-14 reactive CD4+ T cells in vivo, the time course of these cells appearing in pancreas and peripheral, and the T cell repertoire of We-14 reactive T cells. We will also study how Chromogranin A is processed in pancreas.
Frances Crawford, Research Specialist 3
I oversee the lab’s protein biochemistry core facility. I am the lab liaison for baculovirus-expressed proteins in insect cells, including MHC Class II’s, T Cell Receptors, MHC Class II Tetramers and T Cell Receptor multimers.
Anatoly (Tolya) Rubtsov, PhD, Research Associate
My long-term research interest is in uncovering the role of genetic, molecular and cellular components in the development and progression of autoimmune diseases and the crosstalk between these components. My current work is focused on the phenomenon of general predisposition among females to many autoimmune diseases. During my work I identified a particular, previously unknown, population of B cells that was found at a much higher frequency in elderly wild type female mice than in young females, or in males of any age. Importantly, this B cell population was also found to be expanded in younger, autoimmune-prone mice and their appearance correlates with the onset of disease in these animals. Understanding the role of this new B cell population in onset and progression of autoimmune diseases is a focus of my current research in Dr. Philippa Marrack laboratory.
Brendan Reed, PhD, Research Associate
Type 1 Diabetes (T1D) is a chronic autoimmune disease characterized by destruction of the insulin producing beta cells present in the pancreatic islets. Over the past few decades we have come to better understand some of the immunological, environmental, and genetic factors that contribute to the development of T1D. A hallmark of the immune based component of the disease consists of a CD4 T cell mediated attack against beta cell specific antigens in the context of MHC class II molecules, however the exact processes initiating the disease still remain unclear. We are interested in better understanding the antigen processing and presentation events responsible for the CD4 T cell activation that occurs in response to these newly produced, diabetogenic antigens.