Breda Philippe Christophe, Wiech Thorsten, Meyer-Schwesinger Catherine, Grahammer Florian, Huber Tobias, Panzer Ulf, Tiegs Gisa, Neumann Katrin
Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf , Hamburg , Germany.
Institute of Pathology, University Hospital Eppendorf , Hamburg , Germany.
Am J Physiol Renal Physiol. 2019 Jul 1;317(1):F77-F89. doi: 10.1152/ajprenal.00427.2018. Epub 2019 Apr 24.
In immune-mediated glomerular diseases like crescentic glomerulonephritis (cGN), inflammatory CD4 T cells accumulate within the tubulointerstitial compartment in close contact to proximal and distal tubular epithelial cells and drive renal inflammation and tissue damage. However, whether renal epithelial cell populations play a role in the pathogenesis of cGN by modulating CD4 T cell responses is less clear. In the present study, we aimed to investigate the potential of renal epithelial cells to function as antigen-presenting cells, thereby stimulating CD4 T cell responses. Using a FACS-based protocol that allowed comparative analysis of cortical epithelial cell populations, we showed that particularly proximal tubular epithelial cells (PTECs) express molecules linked with antigen-presenting cell function, including major histocompatibility complex class II (MHCII), CD74, CD80, and CD86 in homeostasis and nephrotoxic nephritis, a murine model of cGN. Protein expression was visualized at the PTEC single cell level by imaging flow cytometry. Interestingly, we found inflammation-dependent regulation of epithelium-expressed CD74, CD80, and CD86, whereas MHCII expression was not altered. Antigen-specific stimulation of CD4 T cells by PTECs in vitro supported CD4 T cell survival and induced CD4 T cell activation, proliferation, and inflammatory cytokine production. In patients with antineutrophil cytoplasmic antibody-associated glomerulonephritis, MHCII and CD74 were expressed by both proximal and distal tubules, whereas CD86 was predominantly expressed by proximal tubules. Thus, particularly PTECs have the potential to induce an inflammatory phenotype in CD4 T cells in vitro, which might also play a role in the pathology of immune-mediated kidney disease.
在诸如新月体性肾小球肾炎（cGN）等免疫介导的肾小球疾病中，炎性CD4 T细胞积聚在肾小管间质区，与近端和远端肾小管上皮细胞紧密接触，从而引发肾脏炎症和组织损伤。然而，肾脏上皮细胞群体是否通过调节CD4 T细胞反应在cGN的发病机制中发挥作用尚不清楚。在本研究中，我们旨在探究肾上皮细胞作为抗原呈递细胞发挥功能从而刺激CD4 T细胞反应的潜力。使用基于流式细胞术的方案对皮质上皮细胞群体进行比较分析，我们发现，尤其是近端肾小管上皮细胞（PTECs）在稳态以及cGN的小鼠模型——肾毒性肾炎中表达与抗原呈递细胞功能相关的分子，包括主要组织相容性复合体II类（MHCII）、CD74、CD80和CD86。通过成像流式细胞术在PTEC单细胞水平观察到蛋白表达。有趣的是，我们发现上皮细胞表达的CD74、CD80和CD86存在炎症依赖性调节，而MHCII表达未改变。体外PTECs对抗原特异性刺激CD4 T细胞可支持CD4 T细胞存活，并诱导CD4 T细胞活化、增殖和炎性细胞因子产生。在抗中性粒细胞胞浆抗体相关性肾小球肾炎患者中，近端和远端小管均表达MHCII和CD74，而CD86主要由近端小管表达。因此，尤其是PTECs在体外有潜力诱导CD4 T细胞出现炎性表型，这也可能在免疫介导的肾脏疾病病理过程中发挥作用。
