Rheumatoid arthritis (RA) is a prevalent autoimmune disorder characterized by chronic inflammatory
processes that lead to joint destruction. Immunologically, autoreactive CD4+ T cells play a central role in
disease pathology and activate B cells leading to pathologic lymphoid aggregates within the synovium and
autoantibody production. Although identifying the molecular targets recognized by pathogenic CD4+ T cells is a
critical first step in understanding the molecular basis of RA, we still do not know the antigenic targets for the
vast majority of synovial CD4+ T cells and how such reactivities relate to autoantibody responses. We have
developed a pipeline for CD4+ T cell antigen discovery in RA that relies on a new, cell-based genetic-screening
technology that enables mapping of TCR specificities at genome scale. Based on our preliminary single-cell
transcriptomic data, we have identified several interesting CD4+ T cell populations in synovial fluid that are
clonally expanded and have begun to discover their TCR targets.
This proposal is a five-year research and training plan with a scientific focus on identifying the antigenic targets
of clonally expanded CD4+ T cells from RA synovium and understanding how such antigens relate to
autoantibody responses. We propose in Aim 1 to map the antigenic epitopes and assess the corresponding
HLA-restriction of clonally expanded synovial CD4+ TCRs by performing peptidome-wide antigen discovery
screens. Aim 2 dissects T cell-B cell collaboration in the arthritic joint by interrogating antibody repertoire
binding specificities and performing CD4+ T cell-B cell co-culture assays. Finally in Aim 3, we will engineer an
antigen discovery platform to enable our ability to uncover synovial TCR reactivities against
citrullinated-peptide antigens, a prominent post-translational modification observed in RA.
This study combines cutting-edge genetic and transcriptomic technologies with mechanistic work to critically
evaluate the antigen-specific landscape of RA. It will provide the candidate new training in several scientific
areas to pursue translational immunology research. The candidate’s immediate career development goals are
to gain experience with bioinformatic analysis, antibody profiling technologies, and human immunology assays.
A specific career development plan is described by both the candidate and the mentors, Dr. Stephen Elledge,
an expert in functional genomics and technology development, and Dr. Michael Brenner MD, an expert in
lymphocyte biology and RA, taking advantage of the powerful resources available at Brigham and Women’s
Hospital and Harvard Medical School. The candidate’s long-term career goal is to attain a tenure-track faculty
position leading a diverse group of collaborative scientists dedicated to studying antigen specific immune
responses in rheumatic and autoimmune diseases and their potential applications for therapy.