A Role for Human Renal Tubular Epithelial Cells in Direct Allo-Recognition by CD4+ T-Cells and the Effect of Ischemia-Reperfusion

Int J Mol Sci. 2021 Feb 9;22(4):1733. doi: 10.3390/ijms22041733.


Direct allorecognition is the earliest and most potent immune response against a kidney allograft. Currently, it is thought that passenger donor professional antigen-presenting cells (APCs) are responsible. Further, many studies support that graft ischemia-reperfusion injury increases the probability of acute rejection. We evaluated the possible role of primary human proximal renal tubular epithelial cells (RPTECs) in direct allorecognition by CD4+ T-cells and the effect of anoxia-reoxygenation. In cell culture, we detected that RPTECs express all the required molecules for CD4+ T-cell activation (HLA-DR, CD80, and ICAM-1). Anoxia-reoxygenation decreased HLA-DR and CD80 but increased ICAM-1. Following this, RPTECs were co-cultured with alloreactive CD4+ T-cells. In T-cells, zeta chain phosphorylation and c-Myc increased, indicating activation of T-cell receptor and co-stimulation signal transduction pathways, respectively. T-cell proliferation assessed with bromodeoxyuridine assay and with the marker Ki-67 increased. Previous culture of RPTECs under anoxia raised all the above parameters in T-cells. FOXP3 remained unaffected in all cases, signifying that proliferating T-cells were not differentiated towards a regulatory phenotype. Our results support that direct allorecognition may be mediated by RPTECs even in the absence of donor-derived professional APCs. Also, ischemia-reperfusion injury of the graft may enhance the above capacity of RPTECs, increasing the possibility of acute rejection.

Keywords: CD4+ T-cells; direct allorecognition; ischemia-reperfusion; kidney transplantation; rejection; renal tubular epithelial cells.

MeSH terms

  • Allografts / cytology
  • Allografts / immunology
  • Allografts / pathology
  • Antigen Presentation
  • CD4-Positive T-Lymphocytes / immunology
  • Cells, Cultured
  • Coculture Techniques
  • Epithelial Cells / immunology*
  • Graft Rejection / immunology*
  • Graft Rejection / pathology
  • Humans
  • Isoantigens / immunology
  • Kidney Transplantation / adverse effects*
  • Kidney Tubules, Proximal / cytology
  • Kidney Tubules, Proximal / immunology*
  • Kidney Tubules, Proximal / pathology
  • Lymphocyte Activation
  • Primary Cell Culture
  • Reperfusion Injury / immunology*
  • Reperfusion Injury / pathology
  • Transplantation, Homologous / adverse effects


  • Isoantigens