Expression of the transcription factor Klf6 by thymic epithelial cells is required for thymus development
Justin Malin, Gustavo Ulises Martinez‐Ruíz, Yongge Zhao, Susannah C. Shissler, Jennifer E. Cowan, Yi Ding, Abigail Morales‐Sánchez, Masaki Ishikawa, Marieke Lavaert, Arundhoti Das, Donna Butcher, Andrew Warner, Melissa Kallarakal, Jingqiu Chen, Noémi Kedei, Michael C. Kelly, Lauren Brinster, David Allman, Avinash Bhandoola
Abstract
Thymic epithelial cells (TEC) control T cell development and play essential roles in establishing self-tolerance. By using Foxn1-Cre –driven ablation of Klf6 gene in TEC, we identified Klf6 as a critical factor in TEC development. Klf6 deficiency resulted in a hypoplastic thymus—evident from fetal stages into adulthood—in which a dramatic increase in the frequency of apoptotic TEC was observed. Among cortical TEC (cTEC), a previously unreported cTEC population expressing the transcription factor Sox10 was relatively expanded. Within medullary TEC (mTEC), mTEC I and Tuft-like mTEC IV were disproportionately decreased. Klf6 deficiency altered chromatin accessibility and affected TEC chromatin configuration. Consistent with these defects, naïve conventional T cells and invariant natural killer T cells were reduced in the spleen. Late stages of T cell receptor–dependent selection of thymocytes were affected, and mice exhibited autoimmunity. Thus, Klf6 has a prosurvival role and affects the development of specific TEC subsets contributing to thymic function.