Lymphatic endothelial Tbx1 promotes an immunosuppressive microenvironment to facilitate post-myocardial infarction repair

Wang, W., Li, X., Ding, X., Xiong, S., Hu, Z., Lu, X., Zhang, K., Zhang, H., Hu, Q., Lai, K.S., Chen, Z., Yang, J., Song, H., Wang, Y., Wei, L., Xia, Z., Zhou, B., He, Y., Pu, J., Liu, X., Ke, R., Wu, T., Huang, C., Baldini, A., Zhang, M., Zhang, Z., 2023. Lymphatic endothelial transcription factor Tbx1 promotes an immunosuppressive microenvironment to facilitate post-myocardial infarction repair. Immunity 1–16.

Summary

The heart is an autoimmune-prone organ. It is crucial for the heart to keep injury-induced autoimmunity in check to avoid autoimmune-mediated inflammatory disease. However, little is known about how injury-induced autoimmunity is constrained in hearts.

Here we reveal an unknown intramyocardial immunosuppressive program driven by Tbx1, a DiGeorge syndrome disease gene that encodes a T-box transcription factor. We found induced profound lymphangiogenic and immunomodulatory gene expression changes in lymphatic endothelial cells (LECs) after myocardial infarction (MI). The activated LECs penetrated the infarcted area and functioned as intramyocardial immune hubs to increase the numbers of tolerogenic dendritic cells (tDCs) and regulatory T cells (Tregs) through the chemokineCcl21 and integrin Icam1, thereby inhibiting the expansion of autoreactive CD8+ T cells and promoting reparative macrophage expansion to facilitate post-MI repair.

Mimicking its timing and implementation may be a novel approach to treating autoimmunity-mediated cardiac diseases. Experimental design: We generated a Tbx1FlagSBP allele to perform Tbx1 ChIP experiments to identify potential transcriptional targets of Tbx1. A total of 7,147 peaks were enriched compared to the input control, 26.7% of which contained the consensus T-box binding motif.

To filter out injury-activated Tbx1 binding peaks, we compared our data with cardiac endothelial-specific ATAC-seq data from uninjured hearts (Yucel et al., 2020). The functional annotation of genes associated with Tbx1 peaks or Tbx1 ChIP-seq-only peaks showed a strong enrichment for genes involved in immune tolerance, autoimmune response, T cell activation, endothelial cell growth and migration, consistent with transcriptional analysis.

These results suggested that the aforementioned lymphangiogenic and immunomodulatory genes were direct targets of Tbx1.