Extended Data Fig. 9: Graphical summary of the developmental stages of mTECs and the functional roles of microfoldTECs and endoTECs.

Fate mapping, as well as developmental trajectories, indicate that mTEC mimetics succeed the mTEC-II stage—with the exception of myoTEC, which seem to bifurcate from mTEC-I. Our findings indicate that, aside from roles in the establishment of central tolerance, mimetic TECs also have functional roles in thymus homeostasis and are involved in complex cellular networks, as exemplified by a specialized niche created by microfoldTECs. Specifically, microfoldTECs create such a ‘hub’ for antigen transfer and cell development by bringing into close proximity thymic B cells, CX3CR1⁺ APCs and thymic endothelium. The attraction of thymic B cells to microfoldTECs is dependent on the CCL20–CCR6 chemokine axis, and CX3CR1⁺ APCs then promote the subsequent differentiation of thymic B cells into IgA⁺ isotype-switched PCs through APRIL signalling. Concurrently, thymic B cells promote the development of microfoldTECs, which, in turn, associate with CD31⁺ endothelial cells to enable antigen transfer to thymic APCs. Furthermore, microfoldTECs can suppress mTEC development, including their own, through OPG-mediated suppression of RANK signalling. An important influence on thymic size comes from the secretion of metabolic hormones by endoTECs that modulate thymic involution through paracrine secretion of ghrelin.