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Kidney Week

Abstract: PO0222

Selective Expansion of Kidney Double-Negative T Cells Is Driven by Renal Tubular Epithelial Cells Through Direct Cell-Contact and by Soluble Mediators

Session Information

  • AKI Mechanisms - 3
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Sadasivam, Mohanraj, Johns Hopkins University, Baltimore, Maryland, United States
  • Noel, Sanjeev, Johns Hopkins University, Baltimore, Maryland, United States
  • Gharaie, Sepideh, Johns Hopkins University, Baltimore, Maryland, United States
  • Kurzhagen, Johanna T., Johns Hopkins University, Baltimore, Maryland, United States
  • Hamad, Abdel, Johns Hopkins University, Baltimore, Maryland, United States
  • Rabb, Hamid, Johns Hopkins University, Baltimore, Maryland, United States
Background

Kidney TCRα/β+CD4-CD8-CD1d- double negative (DN) lymphocytes are a recently recognized unconventional T cell population with important roles in AKI and possibly other diseases like lupus. DN T cells expand after experimental AKI and exogenous delivery improves outcome. However, mechanisms underlying their regulation and expansion in the kidney are poorly understood. Here, we demonstrate a direct role for renal tubular epithelial cells (RTEC) in regulating homeostasis of kidney DN T cells.

Methods

Age-matched B6 WT, MHC I KO, MHC II KO and DKO (MHC I and II KO) mice were studied. T cell functional assays and an in-vitro co-culture system were used to investigate the functional relationship between RTEC and DN T cells. RTECs were isolated, purified and cultured in collagen-coated plates. Lymphocytes from both kidney and periphery were isolated, co-cultured with RTEC and analyzed by FACS.

Results

DN T cells were anergic when cultured alone, even after stimulation with anti-CD3/CD28, but spontaneously proliferated when co-cultured with RTEC (DN; 1.2 ± 0.6% vs RTEC+DN; 13.8 ± 3.5%, p≤0.0001). Expansion was due to increased proliferation and decreased apoptosis of DN T cells. RTEC mediated expansion of DN T cells occurred by multiple mechanism including direct cell-contact and secretion of IL-7. Although activation of T cells required direct TCR crosslinking, activation of DN T cells was TCR-MHC independent as indicated by the ability of RTEC from mice lacking MHC class-I, class-II or DKO mice to induce proliferation of DN T cells (DN; 2.1 ± 0.8% vs RTEC (WT)+DN; 17.1 ± 1.5%, vs RTEC (MHC I KO)+DN; 21.2 ± 0.5%, vs RTEC (MHC II KO)+DN; 17.9 ± 1.8%, vs RTEC (DKO)+DN; 32.8 ± 0.3%, p≤0.0001). Reciprocally, DN T cells increased survival of RTEC as demonstrated using in-vitro assays. Our ongoing experiments are focusing on identifying surface molecules involved in mediating interactions between DN T cells and RTEC.

Conclusion

These results demonstrate a previously unknown functional relationship between RTEC and DN T cells that may explain the selective accumulation of DN T cells in the kidney and roles in normal and diseased kidney. The results have important implications for developing strategies to ameliorate AKI by promoting the survival of kidney DN T cells.

Funding

  • NIDDK Support