The Ohio State University Columbus, OH, United States
Latha Prabha Ganesan, Shane Bruckner, Noushin Saljoughian, James Turman, Murugesan Rajaram, Brad Rovin, Wael Jarjour and Samir Parikh, The Ohio State University, Columbus, OH
Background/Purpose: The pathogenesis of lupus nephritis (LN) is incompletely understood stalling progress and resulting in suboptimal patient outcomes. We previously identified a novel inflammatory dendritic cells (InfDC) accumulating in the peri-glomerular space adjacent to CD3+ T cells forming an immunologic synapse in human kidney biopsies at LN flare. Here, we aim to describe the T cell phenotype(s) in cross-talk with these infDC during LN flare. Characterizing these T cells will further our understanding of the major immune cells driving local inflammatory damage during LN.
Methods: Multi-color flow cytometry analysis was performed using antibodies against various immune cell markers, comparing proteinuria NZM 2410 mice and human-chimeric lupus mouse (Hu-lupus) mice with pre-proteinuric NZM (pre-prot-NZM) and humanized healthy (Hu-healthy) mice, respectively.
Results: FACS analysis of T cell phenotypes identified upregulation of double negative (CD4-CD8-) (DN) T cells, but not Th1 or Th17, in prot-NZM compared to pre-proteinuric. Also, the DN T cell frequencies paralleled infDC in the intra-renal space and the expression of both cell types correlated with proteinuria. There was no correlation between infDC and DN T cell kidney expression and proteinuria in lymph nodes or spleen. To relate our findings with human LN, we studied Hu-lupus mice and found significantly higher infDC and DN T cell expression compared to Hu-healthy mice. Importantly, the majority of CD3+ cells in the Hu-lupus mice were TCRαb+TCRgd-CD4-CD8-PD1+, suggesting a subtype of DN T that are known to be self-reactive and proinflammatory.
Conclusion: In this study, we demonstrate an increase in a novel subtype of pro-inflammatory DN T adjacent to infDC in NZM model of LN and in a humanized mouse model of LN. These infDC, DN T cell subtype and their relationship have not been previously described. These findings enhance our understanding of the mechanisms that drive intra-renal inflammation during LN. Targeting infDC or their associated DN T cell phenotype may attenuate renal inflammation and improve outcomes in LN.
Disclosures: L. Ganesan, None; S. Bruckner, None; N. Saljoughian, None; J. Turman, None; M. Rajaram, None; B. Rovin, AstraZeneca, Aurinia, Biogen, Genetech, Janssen, Lupus Foundation of America, GlaxoSmithKlein(GSK); W. Jarjour, None; S. Parikh, Bristol-Myers Squibb(BMS), GlaxoSmithKlein(GSK), Aurinia, Aurinia, Alexion, Kezar life sciences, NIH-NIDDK, EMD-Serono.
