BACKGROUND: NK cell CD16a and T cell CD3 activate shared pathways. Since NK cell CD16a activation occurs in antibody-mediated rejection (ABMR) and T cell CD3 activation occurs in T cell mediated rejection (TCMR), we hypothesized that shared effector lymphocyte activation events must occur in these diseases.

METHODS: To map shared CD16a/CD3-inducible molecules in vitro, primary human NK and CD8 T cells were cultured +/- CD16a or CD3 stimulation respectively. We measured global mRNA expression changes with microarrays, and assayed production of 28 soluble proteins in supernatants. T/NK-selective mRNAs were identified by examining expression in a primary human cell panel. In vivo expression of shared mRNAs in rejection was examined in kidney transplant indication biopsies (N=418).

RESULTS: Four hours stimulation induced 231 shared activation transcripts in both T and NK cells (>2x vs unstim. FDR<0.05). The mRNAs most increased in both cell types included cytokines IFNG, TNF, GM-CSF; chemokines CCL3, CCL4, XCL1; and membrane proteins such as 4-1BB and CD160. Both cell types produced 5/28 proteins after stimulation (IFNG, TNF, GM-CSF, CCL3, CCL4; p=1×10^-5) and did not produce 23/28 (XCL1 not assayed). Whereas many shared mRNAs were expressed in other cell types, IFNG, XCL1, 4-1BB, and CD160 were selective for activated T and NK cells. All 4 were increased in and highly associated with ABMR and TCMR.Differential mRNA signal strengths in vitro between T and NK cells were reflected in vivo between TCMR and ABMR: CD160 had 11x higher expression in stimulated NK cells vs stimulated T cells in vitro and was more associated with ABMR than with TCMR. IFNG showed the opposite pattern.

CONCLUSIONS: NK CD16a and T cell CD3 stimulation induce highly shared mRNA and effector cytokine production. T/NK-selective mRNA expression in biopsies indicates that T and NK cell activation events are shared in ABMR and TCMR. Effector lymphocyte activation events in rejection are thus surprisingly conserved in TCMR and ABMR despite differences in triggering mechanisms and location. Selectivity of CD160 for NK cells and ABMR makes it a candidate marker for specifically assessing effects of treatment on NK cell activation in ABMR.

CITATION INFORMATION: Parkes M, Halloran P, Hidalgo L. CD16a-Activated NK Cells in ABMR Are Highly Similar to CD3-Activated Effector T Cells in TCMR. Am J Transplant. 2017;17 (suppl 3).

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