Mechanistic Sharing Between NK Cells in ABMR and Effector T Cells in TCMR

Abstract

Human organ allograft rejection depends on effector lymphocytes: NK cells in antibody-mediated rejection (ABMR) and effector T cells in T cell-mediated rejection (TCMR). We hypothesized that NK cell CD16a stimulation and CD8 T cell TCR/CD3 stimulation represent highly similar effector systems, and should lead to shared molecular changes between ABMR and TCMR. We studied similarity between soluble proteins and the transcripts induced in CD16a stimulated NK cells and TCR/CD3-stimulated T cells in vitro. Of 30 soluble mediators tested, CD16a-activated NK cells and CD3/TCR activated T cells produced the same limited set of five mediators-CCL3, CCL4, CSF2, IFNG, and TNF-and failed to produce 25 others. Many transcripts increased in stimulated NK cells were also increased in CD3-stimulated CD8 T cells (FDR < 0.05), including IFNG, CSF2, CCL3, CCL4, and XCL1. We hypothesized that shared transcripts not produced by other cell types should be expressed both in ABMR and TCMR kidney transplant biopsies. CD160, XCL1, TNFRSF9, and IFNG were selective for TCR/CD3-activated T cells and CD16a-NK cells and all were strongly increased in ABMR and TCMR. The molecules such as CD160 and XCL1 shared between NK cells in ABMR and effector T cells in TCMR may hold insights into important rejection mechanisms.

Pretransplant transcriptomic signature in peripheral blood predicts early acute rejection

“…Importantly, our transcriptional profile, developed to detect cellular EAR, was also associated with increased risk for de novo DSAs and/or ABMR. This finding is in line with recent evidence that AMBR and T cell receptor share many molecular transcripts (35,36). Our data suggest that a low risk score at the time of transplant identifies individuals whose chances of developing immunological events damaging to the graft are remote, thereby suggesting that they may need lower doses of potentially toxic antirejection therapies aimed at preventing acute rejection.…”

Review: The transcripts associated with organ allograft rejection

“…17,27,28 We believe that the ABMRselective transcripts have weaker associations (P-values) than the TCMR-selective transcripts because the ABMR process is largely con- with evidence for NK CD16a Fc receptor signaling. 1,29,31 ABMR-associated transcripts in heart transplant endomyocardial biopsies are very similar to a mix of the universal transcripts and ABMR-selective transcripts (eg, CXCL11, ROBO4) in kidney transplants with ABMR. 32,33 These results suggest models for TCMR and ABMR, 1,34 summarized here to encourage experimental validation.…”

“…In TCMR, the cognate effector T cells engage antigen on endothelium or antigen presenting cells (APC) prior to transendothelial migration 35,36 probably similar to those in the T cell receptor-activated effector T cell in the interstitium, eg, IFNG production and CD160 expression. 31 In contrast to TCMR, ABMR initially induces more endothelial injury but little parenchymal injury (which is why ABMR is often relatively silent clinical problem).…”

“…The molecular events in the CD16a-activated NK cell inside the capillary areprobably similar to those in the T cell receptor-activated effector T cell in the interstitium, eg, IFNG production and CD160 expression 31. ABMR-selective transcripts are expressed in NK cells (SH2D1B, GNLY, FGFBP2, CD160), endothelial cells (DARC, ROBO4, CDH5, CDH13), or are IFNG-inducible in endothelium (eg, PLA1A and CXCL11).…”

Expansion of CD4 phenotype among CD160 receptor‐expressing lymphocytes in murine pregnancy

“…What factors determine this CD4 + T‐cell expansion among CD160 + lymphocytes and what is their real function in the maternal‐foetal unit remains an open question. Parkes et al found that CD160 expression is selective for stimulated T cells during T‐cell‐mediated rejection in human allograft transplantation. In accordance with this observation, decidual lymphocytes during maternal‐foetal tolerance in pregnant mice did not show increased CD160 expression compared to non‐pregnant endometrial counterparts.…”