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

Abstract

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.

Human PD-L1 overexpression decreases xenogeneic human T-cell immune responses towards porcine kidneys

“…The graft endothelium is the first immune checkpoint between the recipient’s immune system and the renal graft ( 38 ). However, recent studies also indicate that renal proximal tubular epithelial cells may also be directly recognized by T cells, which may immediately contribute to rejection ( 39 , 40 ). Our immunohistochemistry analyses after EVKP indicate the presence of human T-cell focal adhesions in different kidney regions where the recognition of xenoantigens may occur.…”

“…The graft endothelium is the first immune checkpoint between the recipient's immune system and the renal graft (38). However, recent studies also indicate that renal proximal tubular epithelial cells may also be directly recognized by T cells, which may immediately contribute to rejection (39,40) cells under the renal capsule. Compared to the mock-transfected control cells, which showed scattered to moderate T-cell infiltration after 7 days, the number of infiltrated T cells remained low in the rats transplanted with hPD-L1 cells (41).…”

Molecular Aspects of Renal Immunology: Current Status and Future Perspectives

“…This Special Issue includes an experimental study by Eleftheriadis et al [ 10 ] which challenges the above generally accepted paradigm in cultures of primary human renal proximal tubular epithelial cells (RPTECs). In the study, all the required molecules for CD4+ T cell activation (HLA-DR, CD80, and ICAM-1) were detected RPTECs.…”