GSE168163
Single-cell profiling of T lymphocytes in deficiency of adenosine deaminase 2
Background and methods: Deficiency of adenosine deaminase 2 (DADA2) is the first molecularly described monogenic vasculitis syndrome. DADA2 is caused by autosomal-recessive loss-of-function mutations in the ADA2 gene (previously known as CECR1). Vasculitis, vasculopathy and inflammation are dominant clinical features of this disease; however wide spectrum of clinical manifestations includes immunodeficiency, lymphoproliferation, as well as hematologic manifestations. ADA2 is primarily secreted by stimulated monocytes and macrophages. It has been shown that monocytes differentiation to macrophages, and neutrophils play a pathogenic role in DADA2, but little is known about T lymphocytes in this disease. Results: We performed combined single cell RNA sequencing and TCR sequencing to profile T cell repertoire in ten patients with DADA2. Although there are no significant alterations of T cell subsets, we observed activation of both CD8+ and CD4+ T cells, and inflammatory status in these patients. We did not observe clonal expansion of T cells: majority TCRs are expressed at basal level in patients and healthy donors. TCR usage is individual-specific in patients and not disease-specific, indicating unlikely a common pathogenic background or predisposition to a common pathogen in this cohort of patients. We recognized activation of interferon pathways as signature of T cells, and STAT1 as a hub gene in the gene network of T cell activation and cytotoxicity. Overall, T cells in DADA2 patients have altered cell-cell interactions with monocytes, as compared to that in healthy donors, many of these ligand-receptor interactions likely drive upregulation of STAT1 in both T cells and lymphocytes in patients. Conclusion: In conclusion, our single cell analysis of T cells discloses subsets, clonality and transcriptome of a previously undercharacterized cell type in DADA2. Activation of immune response especially IFN pathways remain the core signature of T cells and monocytes. Modulation of IFN pathway, as well as ligand-receptor pairs between immune cells may contribute a novel and directed therapeutic approach in the treatment of DADA2. Overall design: RNA profiles of single peripheral blood T cells of 10 DADA2 patients and 5 healthy donors were generated by deep sequencing using Illumina HiSeq 3000