Abstract
Systemic inflammatory response syndrome describes a heterogeneous group of cytokine storm disorders, with different immunogens and cytokines leading to variations in organ pathology. The severe inflammation generated by the cytokine storm results in widespread organ pathology including alterations in T- and B-lymphocyte counts. This study explores the roles of TLR9 and IFN-γR stimulation in decreasing T- and B-cell lymphopoiesis in a mouse model of hyperinflammation. We demonstrate that early B-cell lymphopoiesis is severely compromised during TLR9- and IFN-γ-driven hyperinflammation from the Ly-6D(+) common lymphoid progenitor stage onwards with different effects inhibiting development at multiple stages. We show that TLR9 signaling directly decreases in vitro B-cell yields while increasing T-cell yields. IFN-γ also directly inhibits B-cell and T-cell differentiation in vitro as well as when induced by TLR9 in vivo. Microarray and RT-PCR analysis of Ly-6D(-) common lymphoid progenitors point to HOXa9 and EBF-1 as transcription factors altered by TLR9-induced inflammation. Our work demonstrates both cellular and molecular targets that lead to diminished B-cell lymphopoiesis in sustained TLR9- and IFN-γ-driven inflammation that may be relevant in a number of infectious and autoimmune/inflammatory settings.