PRDM1 Drives Human Primary T Cell Hyporesponsiveness by Altering the T Cell Transcriptome and Epigenome

Background: T cell hyporesponsiveness is crucial for the functional immune system and prevents the damage induced by alloreactive T cells in autoimmune pathology and transplantation. Methods: We detected the phenotype of PRDM1 overexpressed human primary T cells. To investigate the molecular mechanisms of PRDM1 regulating T cells, we performed RNA-seq, MethylationEPIC BeadChip array, CUT&Tag and ATAC-seq in PRDM1 overexpressed human primary T cells. Findings: Overexpression of PRDM1 in primary T cells expanded Treg cell subsets and increased the secretion of IL-4, while decreased expression had the opposite effects. Integrated multiomics analysis showed that PRDM1 directly upregulated T cell inhibitory genes such as CD244, KLF2 and KLRD1 and downregulated the T cell activation gene IL2, indicating that PRDM1 could promote a tolerant transcriptional profile in primary T cells. Binding motifs of key T cell function regulators, such as FOS, JUN and AP-1, were enriched in PRDM1 binding sites and that PRDM1 altered the chromatin accessibility of these regions. Furthermore, the PRDM1 expression level in allografts was negatively related to acute graft-versus-host disease (aGVHD) occurrence after hematopoietic stem cell transplantation (HSCT). Interpretation: Our systematic multiomics analysis found that the transcription factor (TF) PRDM1 acts as a pioneer TF and master regulator during T cell hyporesponsiveness in human primary T cells. These results demonstrated that PRDM1 is sufficient for inducing T cell hyporesponsiveness and could be a predictive biomarker for HSCT prognosis. Funding: This work was partly supported by grants from the National Key Research and Development Program of China (2017YFA0104500), Innovative Research Groups of the National Natural Science Foundation of China (No. 81621001), Key Program of the National Natural Science Foundation of China (No.81530046, 81930004), Beijing Municipal Natural Science Foundation (Grant No. 7204319). Declaration of Interest: None to declare. Ethical Approval: The study has been approved by the Ethics Committee of Peking University People's Hospital, and written informed consent from all subjects was obtained