The recently published model for T cell-mediated rejection (TCMR) of kidney allografts proposes that the major unit of cognate recognition in TCMR is effector T cells engaging donor antigen on dendritic cells (DC) and macrophages (MAC). ADAMDEC1, CXCL13 and CCL18 are the top MAC transcripts distinguishing TCMR from antibody-mediated rejection. We hypothesized that in human TCMR, ADAMDEC1, CXCL13 and CCL18 expression is induced in MAC by interaction with infiltrating T cells. We studied the expression of these transcripts in vitro in cultured monocyte-derived MAC and DC, and in response to stimulation. Using RT-PCR, MAC had strong expression of ADAMDEC1, CXCL13 and CCL18. DC did not express ADAMDEC1, but expressed CCL18 and CXCL13. Stimulation with CD40L, TNF and LPS increased the expression of these transcripts in MAC, but IFNG did not. We further studied the expression of ADAMDEC1, CXCL13 and CCL18 in MAC cocultured in transwell with autologous anti-CD3 stimulated effector T cells. Using RT-PCR (figure1), ADAMDEC1 and CCL18 were expressed in control MAC (cultured alone) but not in control T cells (cultured alone). ADAMDEC1 and CCL18 expression increased (p<0.0001) in MAC cocultured with T cells compared to control MAC, but was not detected in T cells cocultured with MAC. CXCL13 was expressed in control MAC and T cells, and expression increased (p<0.0001) in MAC cocultured with T cells, but not in T cells cocultured with MAC. Thus we propose that expression of MAC transcripts ADAMDEC1, CXCL13 and CCL18 in human kidney allografts with TCMR is induced in differentiated MAC by direct contact with infiltrating T cells and/ or soluble factors (not IFNG) released upon MAC interaction with infiltrating T cells. Our data suggests that the molecular phenotype of MAC in TCMR reflects interactions with antigen-triggered T cells or their soluble factors released during TCMR.

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