TY - JOUR

T1 - Back signaling of HLA class I molecules and T/NK cell receptor ligands in epithelial cells reflects the rejection-specific microenvironment in renal allograft biopsies

AU - Egelkamp, Johanna

AU - Chichelnitskiy, Evgeny

AU - Kühne, Jenny F.

AU - Wandrer, Franziska

AU - Daemen, Kerstin

AU - Keil, Jana

AU - Bräsen, Jan Hinrich

AU - Schmitz, Jessica

AU - Bellmàs-Sanz, Ramon

AU - Iordanidis, Susanne

AU - Katsirntaki, Katherina

AU - Hake, Kevin

AU - Akhdar, Ali

AU - Neudörfl, Christine

AU - Haller, Hermann

AU - Blume, Cornelia

AU - Falk, Christine S.

N1 - Funding information: This work was supported by the German Research Foundation DFG, SFB738, B3 (CSF), the German Ministry for Education and Research BMBF, IFB-Tx BMBF 01EO1302 (CSF), the German Center for Infection Research DZIF TTU-IICH (CSF), the Ministry of Lower Saxony for Research and Art (MWK), Project “gender sensible medicine in kidney transplantation” and the Jackstädt foundation (JHB, JS).

PY - 2019/9/26

Y1 - 2019/9/26

N2 - The role of endothelial cells in the pathophysiology of antibody-mediated rejection after renal transplantation has been widely investigated. We expand this scenario to the impact of epithelial cells on the microenvironment during rejection. Primary proximal tubular epithelial cells were stimulated via HLA class I, CD155 and CD166 based on their potential signal-transducing capacity to mediate back signaling after encounter with either T/NK cells or donor-specific antibodies. Upon crosslinking of these ligands with mAbs, PTEC secreted IL-6, CXCL1,8,10, CCL2, and sICAM-1. These proteins were also released by PTEC as consequence of a direct interaction with T/NK cells. Downmodulation of the receptor CD226 on effector cells confirmed the involvement of this receptor/ligand pair in back signaling. In vivo, CD155 and CD166 expression was detectable in proximal and distal tubuli of renal transplant biopsies, respectively. The composition of the protein microenvironment in these biopsies showed a substantial overlap with the PTEC response. Cluster and principal component analyses of the microenvironment separated unsuspicious from rejection biopsies and, furthermore, ABMR, TCMR, and borderline rejection. In conclusion, our results provide evidence that epithelial cells may contribute to the rejection process and pave the way to a better understanding of the pathomechanisms of kidney allograft rejection.

AB - The role of endothelial cells in the pathophysiology of antibody-mediated rejection after renal transplantation has been widely investigated. We expand this scenario to the impact of epithelial cells on the microenvironment during rejection. Primary proximal tubular epithelial cells were stimulated via HLA class I, CD155 and CD166 based on their potential signal-transducing capacity to mediate back signaling after encounter with either T/NK cells or donor-specific antibodies. Upon crosslinking of these ligands with mAbs, PTEC secreted IL-6, CXCL1,8,10, CCL2, and sICAM-1. These proteins were also released by PTEC as consequence of a direct interaction with T/NK cells. Downmodulation of the receptor CD226 on effector cells confirmed the involvement of this receptor/ligand pair in back signaling. In vivo, CD155 and CD166 expression was detectable in proximal and distal tubuli of renal transplant biopsies, respectively. The composition of the protein microenvironment in these biopsies showed a substantial overlap with the PTEC response. Cluster and principal component analyses of the microenvironment separated unsuspicious from rejection biopsies and, furthermore, ABMR, TCMR, and borderline rejection. In conclusion, our results provide evidence that epithelial cells may contribute to the rejection process and pave the way to a better understanding of the pathomechanisms of kidney allograft rejection.

KW - basic (laboratory) research/science

KW - biomarker

KW - immune regulation

KW - immunobiology

KW - immunosuppression/immune modulation

KW - kidney transplantation/nephrology

KW - natural killer (NK) cells/NK receptors

KW - rejection: antibody-mediated (ABMR)

KW - T cell biology

UR - http://www.scopus.com/inward/record.url?scp=85072717299&partnerID=8YFLogxK

U2 - 10.1111/ajt.15417

DO - 10.1111/ajt.15417

M3 - Article

C2 - 31062482

AN - SCOPUS:85072717299

VL - 19

SP - 2692

EP - 2704

JO - American Journal of Transplantation

JF - American Journal of Transplantation

SN - 1600-6135

IS - 10

ER -