BACKGROUND: CD16α mediates NK cell responses to donor-specific IgG antibodies (DSA), and shares mechanisms with effector T cell receptor (TCR) stimulation. Whether CD16α-inducible transcripts are associated with antibody-mediated rejection (ABMR) relative to other diseases remains unknown; we hypothesized that CD16α-inducible NK transcripts are associated with ABMR vs. disease states without T cell-mediated pathology. METHODS: We cultured primary human NK cells and CD8+ T cells +/- CD16α or CD3 stimulation, respectively, and examined global gene expression changes. We identified the top CD16α-inducible NK transcripts, focused on the 11 expressed >1000 in stimulated NKs (Fig 1A), and examined them in 703 indication biopsies. RESULTS: The 7 CD16-inducible NK transcripts associated with ABMR (p<10^-7) are shown in Fig. 2. These include CD160 and XCL1, which are selective for stimulated NK cells and CD8+ T cells, and thus are also associated with TCMR (Fig 1B). Membrane protein CRTAM promotes IFNG release and cytotoxicity in NK cells and CD8+ effector T cells; chemokines CCL4 and CCL3, Fc-repetor-like protein FCRL3, and TNFRSF9 all reflect shared functions between NK in ABMR and CD8+ T cells in TCMR. CONCLUSIONS: A number of CD16α-inducible transcripts are strongly associated with ABMR, supporting the hypothesis that in ABMR the Fc portions of endothelium-bound DSA trigger NK CD16α, which has the potential to release cytokines and activate cytotoxicity. Many of these are also expressed in TCMR because of the similarity of the signaling systems for CD16 and TCR. Weak ABMR associations of some CD16α-inducible transcripts may reflect additional expression in other cell types and disease states.

CITATION INFORMATION: Parkes M, Halloran P, Hidalgo L. Gene Expression Microarray Analysis of Purified CD16-Stimulated Human NK Cells and Indication Biopsies Supports a CD16-Mediated Role for NK Cells in Antibody-Mediated Kidney Rejection. Am J Transplant. 2016;16 (suppl 3).

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