Role of STAT3 Signaling in GC B Cell Regulation

University Of Louisville, Louisville KY

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Abstract

? DESCRIPTION (provided by applicant): Germinal centers (GCs) are unique microenvironment that has proliferative B cells undergoing class switching, somatic hypermutation, and affinity maturation. Although alternative pathways exist, GCs are the major source of long-lived antibody (Ab)-secreting plasma cells and memory B cells. Previous studies have demonstrated that SLE may develop as a result of enhanced GC activity. Spontaneous GC formation has been found in the lupus-prone mice. In addition, active lupus patients have abnormal GC reactions and increased plasma cells. Therefore, understanding signaling pathways that regulate the GC formation and GC B cell differentiation may identify novel targets for the successful intervention of SLE. The signal transducer and activator of transcription factor 3 (STAT3) signaling pathway is critical for human B cells to differentiate into Ab-secreting plasma cells. Dysregulation of STAT3 pathway has also been implicated in the development of SLE. However, the role of STAT3 in the GC B cell response has been controversial. A previous study has demonstrated that B cell-specific STAT3 deficient mice have lower T- dependent IgG response but display normal GC formation. Paradoxically, GC is the major source of both memory B cells and long-lived plasma cells. One caveat of this study is that they only examined GC response at day 12. Our preliminary studies demonstrated that B cell-specific STAT-3 KO mice had significantly decreased GC formation, GC B cells, and Tfh cells in the later phase (day 21) but not in the early time point (day 14). Furthermore, STAT3-deficient autoreactive B cells had defective autoAb responses and GC B cell differentiation upon immunization. We hypothesize that STAT3 signaling is essential for the maintenance of the GC formation and GC B cell differentiation. Two Aims are proposed to address this hypothesis. Aim 1 determines the mechanisms by which STAT3 signaling regulates the maintenance of the GC formation and GC B cell response using C¿1-cre mice which specifically delete STAT3 in the GC B cells. We will also determine extracellular signals that stimulate STAT3 activation in GC B cells. Aim 2 examines whether B cell intrinsic STAT3 signaling is required for autoAb production and disease progression in lupus-prone MRL/lpr mouse model. In addition, we will use anti-CD19 single chain variable fragment (scFv) miniAb to specifically deliver STAT3 siRNA into B cells in MRL/lpr mice. The therapeutic efficacy of this intervention will be determined. The overall goal of this proposal is to determine how STAT3 signaling regulates the GC formation and GC B cell response and whether ablation of STAT3 signaling specifically in autoreactive B cells provides benefit for lupus treatment.