The Rao lab is focused on modulating pathologic lymphocyte functions to treat human autoimmune diseases. T cells are central regulators in multiple autoimmune diseases, yet defining their key functions in different diseases has been challenging. Our approach involves 2 major steps:
1) First, we use high-dimensional analyses (CyTOF, single cell RNA-seq) of tissue and blood samples from patients with autoimmune diseases to identify the T cell phenotypes that dominate pathologic patient samples.
2) Once we have identified pathologically expanded cell populations, we use in vitro functional analyses, CRISPR/Cas9 gene editing, and murine models to understand the roles of these cell populations in disease pathology.
Using this strategy, we aim to identify new therapeutic targets in human autoimmunity. Our recent studies provide an example of the power of this approach. CyTOF analyses of joint tissue from patients with rheumatoid arthritis revealed a markedly expanded PD-1hi CXCR5- CD4+ T cell population (Rao et al, Nature 2017). Functional and transcriptomic analyses revealed that these cells are uniquely able to infiltrate inflamed tissues and drive B cell responses locally within the tissue, thus we called them ‘T peripheral helper cells’ (Tph cells). We are now evaluating Tph cells as a compelling therapeutic target in rheumatoid arthritis. Ongoing projects in the lab focus on two areas:
Molecular regulation of the ability of T cells to help B cells. Tph cells expanded in rheumatoid arthritis joints produce high levels of IL-21 and CXCL13 and potently drive B cell differentiation into plasma cells; however they differ from Tfh cells in migratory capacity and transcriptional regulation (Rao et al, Nature 2017). We hypothesize that these cells may be a major population driving B cell responses locally in inflamed tissues (Rao, Front Immunol 2018). Our group is now studying 1) the transcriptional control of human Tph cell functions using CRISPR/Cas9 gene-editing, 2) the differences in B cell help provided by human Tfh vs Tph cells, 3) the roles of Tph cells in murine models of arthritis and lupus, 4) the expansion of Tph cells in other autoantibody-associated diseases.
High-dimensional analyses to identify new pathologic T cell populations in autoimmunity. Through CyTOF analyses of PBMCs, we recently identified an expanded CD4+ CD27- HLADR+ cytotoxic T cell population in RA patients that we are now characterizing further (Fonseka and Rao et al, Sci Transl Med, 2018). Our lab is generating and/or analyzing high-dimensional datasets from blood or tissues samples of patients with untreated early lupus, pre-rheumatoid arthritis, and scleroderma, to discover new immune cell populations altered at different phases of human autoimmune diseases.
Hale Building for Transformative Medicine
60 Fenwood Rd., Room 6002R
Boston, MA 02115