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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/inflammatory-dendritic-cell-drive-intra-renal-t-cells-to-double-negative-t-cell-in-lupus-nephritis/