Interaction between kidney senescent cells and CD8+ T lymphocytes in lupus nephritis

Details

Supervisors

Limaye, Nisha

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [120] en sciences biomédicales, à finalité approfondie

Abstract

Lupus nephritis (LN) is a frequent and severe complication of systemic lupus erythematosus (SLE), an autoimmune disease affecting mostly young women. About 5-10% of patients develop end-stage renal disease despite immunosuppressive treatment. So far, it is not possible to identify patients with poor renal outcome and to treat them adequately. It is becoming clear that the LN kidney is not just a passive target of systemic disease but also hosts complex disease mechanisms. These include in situ recruitment of inflammatory cells, as well as pathogenic activity of resident renal cells. Together, these can contribute to renal injury, eventually leading to irreversible fibrosis and loss of kidney function. CD8+ T lymphocytes are emerging as key players in LN, as they may recognize renal neo-antigens and consequently cause tissue damage. Recently, the lab showed an association between p16INK4a-positive cells, a marker of cellular senescence, and renal impairment in LN. In addition, kidney infiltrating CD8+ T cells and p16INK4a-positive cells were spatially co-distributed, suggesting an interaction, possibly pathogenic, between these cells. The aim of this project is to dissect the putative functional interaction between kidney senescent cells and surrounding CD8+ T cells. To do so, the phenotype and T cell receptor (TCR) repertoire of CD8+ T cells, isolated from the high p16INK4a/CD8 positive kidney biopsy of a patient with poor renal outcome, were assessed by single-cell RNA sequencing (scRNA-Seq). A restricted repertoire of highly repeated TCRs was identified, with the 4 most repeated accounting for 21% of all detected TCRs. These TCRα and -β sequences have been reconstructed in silico and expressed in a reporter T cell line for a future functional in vitro cognate antigen-screening assay. For this assay, target cells would be autologous renal progenitor cells (RPC), in which cellular senescence would be induced by various stimuli, or HEK293T cells expressing patient’s human leukocyte antigen (HLA) molecules transduced with a cDNA library from kidney senescent cells. Finally, we assessed whether the observations made in LN patient kidneys also occur in a lupus-prone mouse model, by characterizing cellular senescence and CD8+ T cell infiltration in kidney sections of 21 B6.Sle1.Sle2.Sle3 mice. Interestingly, we observed that samples with more renal damage had significantly higher p16Ink4a and CD8 staining, which in addition are well correlated. This suggests that B6.Sle1.Sle2.Sle3 mice would be a suitable model for further experiments on the potential interaction between CD8+ T cell and kidney senescent cells in LN.