Attenuation of apoptotic cell detection triggers thymic regeneration after damage

• Published in: Cell reports (Cambridge) 2021-10, Vol.37 (1), p.109789-109789, Article 109789
• Main Authors: Kinsella, Sinéad, Evandy, Cindy A., Cooper, Kirsten, Iovino, Lorenzo, deRoos, Paul C., Hopwo, Kayla S., Granadier, David W., Smith, Colton W., Rafii, Shahin, Dudakov, Jarrod A.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; apoptotic cell death; Bone Morphogenetic Protein 4 - metabolism; Female; Interleukin-23 - metabolism; lymphopenia; Male; Mice; Mice, Inbred C57BL; MicroRNAs - metabolism; NOD2; Nod2 Signaling Adaptor Protein - deficiency; Nod2 Signaling Adaptor Protein - genetics; Phosphatidylserines - metabolism; Pyrones - pharmacology; Quinolines - pharmacology; rac1 GTP-Binding Protein - antagonists & inhibitors; rac1 GTP-Binding Protein - metabolism; Rac1 GTPase; Regeneration - drug effects; T cell development; TAM receptors; Thymocytes - cytology; Thymocytes - metabolism; thymus; Thymus Gland - physiology; tissue regeneration
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109789

The thymus, which is the primary site of T cell development, is particularly sensitive to insult but also has a remarkable capacity for repair. However, the mechanisms orchestrating regeneration are poorly understood, and delayed repair is common after cytoreductive therapies. Here, we demonstrate a trigger of thymic regeneration, centered on detecting the loss of dying thymocytes that are abundant during steady-state T cell development. Specifically, apoptotic thymocytes suppressed production of the regenerative factors IL-23 and BMP4 via TAM receptor signaling and activation of the Rho-GTPase Rac1, the intracellular pattern recognition receptor NOD2, and micro-RNA-29c. However, after damage, when profound thymocyte depletion occurs, this TAM-Rac1-NOD2-miR29c pathway is attenuated, increasing production of IL-23 and BMP4. Notably, pharmacological inhibition of Rac1-GTPase enhanced thymic function after acute damage. These findings identify a complex trigger of tissue regeneration and offer a regenerative strategy for restoring immune competence in patients whose thymic function has been compromised. [Display omitted] •NOD2 suppresses the production of the key thymic regenerative factors BMP4 and IL-23•Detection of apoptotic thymocytes by TAM receptors mediates NOD2-dependent suppression•Depletion of thymocytes after acute damage attenuates detection of apoptotic cells•Inhibition of Rac1 promotes thymus repair and T cell reconstitution after damage Delayed lymphopenia is a common feature of many cancer therapies that is predicated on poor regeneration of thymic function. Kinsella et al. identify a trigger of endogenous thymic repair, centered on the detection of apoptotic thymocytes, that can be exploited to improve T cell regeneration after immune-depleting therapies.