An inflammatory loop established between spleen-derived myeloid cells and CD4+ T cells leads to accumulation of long-lived plasma cells that exacerbate lupus autoimmunity

Splenic long-lived plasma cells (PCs) are abnormally numerous and deleterious in systemic autoimmune diseases, yet how they accumulate remains poorly understood. We demonstrate here that a pathological role of spleen-derived CD11b+Gr-1+ myeloid cells (SPMCs) underpins the accumulation of splenic long-lived PCs in a lupus-prone model. SPMCs were a mixture of granulocytic and monocytic myeloid-derived suppressor cells (MDSCs) that were expanded and acquired proinflammatory phenotypes in situ during lupus progression. By promoting the development of IFN-?-secreting and follicular helper T cells, SPMCs licensed CD4+ T cells to be pathologic activators of SPMCs and PCs. SPMCs also directly promoted the survival of PCs by providing B-cell activating factor of the TNF family. The frequency of SPMCs correlated with that of splenic long-lived PCs. Depletion of CD11b+Gr-1+ cells reduced autoantibody production. Thus, our findings suggest that SPMCs expanded in situ establish a positive feedback loop with CD4+ T cells, leading to accumulation of long-lived PCs which exacerbate lupus autoimmunity. Overall design: Roquin(san/+) mice on a C57BL/6 background were originally purchased from Mutant Mouse Regional Resource Center at the University of California at Davis and were maintained in a specific pathogen-free barrier facility at Hanyang University. Total RNA was extracted from CD11+Gr-1hi and CD11+Gr-1lo cells from the spleens (SP) and bone marrow (BM) of approximately 20-wk-old sanroque mice. cDNA libraries were prepared using a TruSeq Stranded mRNA LT Sample Prep kit (Illumina) and sequenced on a NovaSeq 6000 platform using 101 bp paired-read strategy. In total, 8 samples (2 SP Gr-1 hi, 2 SP Gr-1 low, 2 BM Gr-1 hi, 2 BM Gr-1 low) were collected.