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Evidence for CD16a-Mediated NK Cell Stimulation in Antibody-Mediated Kidney Transplant Rejection

Parkes, Michael D. MSc; Halloran, Philip F. MD, PhD; Hidalgo, Luis G. PhD

doi: 10.1097/TP.0000000000001586
Original Basic Science—General

Background Natural killer (NK) cells localize in the microcirculation in antibody-mediated rejection (AMR) and have been postulated to be activated by donor-specific anti-HLA antibodies triggering their CD16a Fc receptors. However, direct evidence for NK cell CD16a triggering in AMR is lacking. We hypothesized that CD16a-inducible NK cell-selective transcripts would be expressed in human AMR biopsies and would offer evidence for CD16a triggering.

Methods We stimulated human NK cells through CD16a in vitro, characterized CD16a-inducible transcripts, and studied their expression in human kidney transplant biopsies with AMR and in an extended human cell panel to determine their selectivity.

Results In NK cells, CD16a stimulation induced increased expression of 276 transcripts (FC > 2x, false discovery rate < 0.05), including IFNG, TNF, CSF2, chemokines, such as CCL3, CCL4, and XCL1, and modulators of NK cell effector functions (TNFRSF9, CRTAM, CD160). Examination in an extended human cell panel revealed that CD160 and XCL1 were likely to be selective for NK cells in AMR. In biopsies, 8 of the top 30 CD16a-inducible transcripts were highly associated with AMR (P < 5 × 10−6): CCL4, CD160, CCL3, XCL1, CRTAM, FCRL3, STARD4, TNFRSF9. Other NK cell transcripts (eg, GNLY) were increased in AMR but not CD16a-inducible, their presence in AMR probably reflecting NK cell localization.

Conclusions The association of CD16a-inducible NK cell-selective transcripts CD160 and XCL1 with biopsies with AMR provides evidence for NK cell CD16a activation in AMR. This raises the possibility of other CD16a-triggered effects that are not necessarily transcriptional, including NK localization and cytotoxicity.

In a retrospective study, Xu et al identify circulating microRNAs that discriminate between acute rejection, bronchiolitis obliterans syndrome and stable pediatric recipients of lung transplantation, and implicate TGFA signaling, T cell-activation and antigen-presentation pathways as discriminating between these clinical states.

1 Alberta Transplant Applied Genomics Centre, Edmonton, AB, Canada.

2 Department of Medicine, Division of Nephrology and Transplant Immunology, University of Alberta, Edmonton, AB, Canada.

3 Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, AB, Canada.

Received 12 August 2016. Revision received 21 October 2016.

Accepted 2 November 2016.

P F Halloran holds shares in Transcriptome Sciences Inc., a company with an interest in molecular diagnostics. The other authors declare no funding or conflicts of interest.

M.D.P. is the primary author of this article and carried out experiments and analyses described within. P.F.H. and L.G.H. are the principal investigators for this study and played significant roles in designing the study, and shaping the content and structure of this article.

Correspondence: Luis G. Hidalgo PhD, D (ABHI), University of Alberta Hospitals Histocompatibility Laboratory 8440 112 St.-WMC 4B4.19 Edmonton, AB, Canada T6G 2B7. (luis.hidalgo@ualberta.ca).

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