Abstract
Myeloid cells are increasingly recognized as major players in transplant rejection. Here, we used a murine kidney transplantation model and single cell transcriptomics to dissect the contribution of myeloid cell subsets and their potential signaling pathways to kidney transplant rejection. Using a variety of bioinformatic techniques, including machine learning, we demonstrate that kidney allograft–infiltrating myeloid cells followed a trajectory of differentiation from monocytes to proinflammatory macrophages, and they exhibited distinct interactions with kidney allograft parenchymal cells. While this process correlated with a unique pattern of myeloid cell transcripts, a top gene identified was
Axl
, a member of the receptor tyrosine kinase family Tyro3/Axl/Mertk (TAM). Using kidney transplant recipients with
Axl
gene deficiency, we further demonstrate that Axl augmented intragraft differentiation of proinflammatory macrophages, likely via its effect on the transcription factor Cebpb. This, in turn, promoted intragraft recruitment, differentiation, and proliferation of donor-specific T cells, and it enhanced early allograft inflammation evidenced by histology. We conclude that myeloid cell
Axl
expression identified by single cell transcriptomics of kidney allografts in our study plays a major role in promoting intragraft myeloid cell and T cell differentiation, and it presents a potentially novel therapeutic target for controlling kidney allograft rejection and improving kidney allograft survival.
In a murine model of allogeneic kidney transplantation, single-cell transcriptomics identifies that myeloid cell Axl expression promotes allograft rejection by inducing inflammatory macrophage differentiation.
