Abstract: FR-PO693

Antirenal CD4+ T Cells Arise in Lupus Nephritis, Are Mainly of the Th1 Phenotype, Are Only Partially Controlled by Their Regulatory Counterparts, and Invade the Inflamed Kidneys

Session Information

Category: Glomerular

  • 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

  • Enghard, Philipp, Charité, Berlin, Germany
  • Tesch, Sebastian, Charité Universitätsmedizin Berlin, Berlin, Germany
  • Abdirama, Dimas, Charité Universitätsmedizin Berlin, Berlin, Germany
  • Riemekasten, Gabriela, University Lübeck, Lübeck, Germany
Background

Lupus nephritis (LN) is associated with local MHC II upregulation and a T cell rich infiltration, suggesting an antigen-specific immune response. However, up to date no renal target antigens are known in LN. Here we report the identification of a set of target autoantigens and characterize the respective CD4+ T cell response.

Methods

Peripheral blood T cells from 57 SLE patients and 11 healthy controls (HC) were analyzed. In an initial cohort T cells were stimulated with kidney lysates from healthy kidneys. Subsequently five candidate autoantigens were identified based on the assumption that a corresponding autoantibody is present and that the respective antigen is upregulated in the inflamed kidney in LN. Enrichment via CD40L expression was performed and intracellular cytokine production was measured with flowcytometry (ARTE method). Regulatory T cells were assessed via CD137 enrichment. Urinary T cells from six patients with active LN were isolated and probed for the presence of autoreactive T cells.

Results

Only marginal T cell reactivity was detectable when stimulating peripheral blood T cells with kidney lysates. In subsequent experiments, a pool of renal candidate autoantigens was used and autoreactive CD4+ T cells were detected in patients with SLE and healthy controls. These cells were mainly IFN-y producing Th1 T cells and were significantly expanded in patients with active LN, compared to inactive SLE patients and HC. IL-4, IL-10 and IL-17 producing antirenal CD4+ T cells were present in lower frequencies, albeit also expanded in patients with active LN. Upon stimulation with renal autoantigens, CD137 expressing Tregs were also detected, and the ratio of IFN-y+ T cells to CD137+ Treg cells was significantly higher in active LN patients and correlated with disease activity. Using T cell libraries we identified Vimentin and Annexin A2 as the main, but not exclusive targets of the antirenal T cell response. Finally, we were able to also detect antirenal T cells in the urine of patients with active LN, indicating renal invasion of these cells.

Conclusion

An antirenal CD4+ T cell response arises in LN. These cells are mainly of the Th1 phenotype, invade the inflamed renal tissue and are only partly controlled by their regulatory counterparts.

Funding

  • Government Support - Non-U.S.