A paracrine mTEC/cTEC FGF21—mTOR signaling axis regulates thymic architecture and T cell development across the lifespan 2260524

Introduction Cortical thymic epithelial cells (cTECs) establish a lymphopoietic thymocyte niche that regulates thymus size and T cell output throughout life. Our recent studies suggest that medullary TEC (mTEC)-derived fibroblast growth factor 21 (FGF21) acts in a paracrine manner to drive temporally distinct patterns of mTORC1 and mTORC2 signaling in cTECs. Thymic overexpression of FGF21 promoted thymus growth, enhanced T cell responsiveness to infection, and reduced indicators of age-associated autoimmunity. However, the cellular mechanisms regulating FGF21-dependent regulation of cTEC function across the lifespan have not been defined. Methods To determine whether cTEC-intrinsic FGF21—mTOR signaling regulates thymic architecture and function, we generated a new mouse model in which β5t-iCre drives cTEC-restricted deletion of the obligate FGF21 co-receptor, Klb, as well as expression of the Confetti multicolor reporter allele (β5t-iCre KlbF/F Confetti). We used flow cytometry and confocal microscopy to assess the kinetics of Klb expression, mTORC1/2 activity, thymic structure, cellular composition, T cell development, and cTEC morphology from birth to middle age in β5t-iCre KlbF/F Confetti mice and littermate controls. Results Together, our results suggest that cTECs directly respond to FGF21 signaling via the Klb receptor, and that mTORC1 and mTORC2 mediate cTEC-intrinsic FGF21 signaling to promote thymus size and function. Conclusion The conclusion is combined with the results.