Modeling T Cell- B Cell Interaction in Rheumatoid Arthritis in a 3D Organoid System

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease that results in joint inflammation and destruction. During the disease progression, synovial fibroblasts and immune cell populations play important roles in joint inflammation and symptom development by secreting inflammatory mediators and further recruiting immune cells, facilitating local tissue destructions in the synovium. Although lymphoid cells such as T peripheral helper (Tph) cells and plasmablasts aggregate in the synovium during RA, a systematic model that focuses on the role of lymphoid interactions between T cells and B cells in the synovium and their role in disease progression has not been established. The current study utilizes a three-dimensional organoid culture model to recapitulate the synovial tissue in-vitro, which contains synovial fibroblasts, memory CD4+ T cells, and memory B cells. First, the study aims to optimize the organoid model by increasing cell viability, optimizing the number and ratio of each cellular compartment, and strengthening the inflammatory responses to recapitulate the inflammatory interactions in the RA synovium. We have consistently created lymphoid aggregations in the organoid that are identifiable by fluorescence imaging and quantifiable by image analysis software, which are further supported by the cytokine secretion profiles. Next, we aim to apply the model to study potential strategies to interfere with the T cell-B cell interactions and to reduce the inflammatory crosstalk. This study provides a versatile model of T cell-B cell interaction for future studies in the context of RA, and it provides new insight into therapeutics design that targets lymphoid interaction, which is central to the inflammatory response in the RA synovium.