TL1A and IL-18 synergy promotes GM-CSF-dependent thymic granulopoiesis in mice

Acute systemic inflammation profoundly disrupts immune function, favoring myelopoiesis over lymphopoiesis. In the thymus, this leads to acute atrophy and impaired T-lymphopoiesis, though the mechanisms beyond direct suppression of T-cell development remain unclear. Here, we demonstrate that TL1A and IL-18 synergistically suppress T-lymphopoiesis while promoting thymic myelopoiesis. Levels of these cytokines were elevated in the thymus during viral-induced atrophy following infection with murine cytomegalovirus (MCMV) or pneumonia virus of mice (PVM). In vivo administration of TL1A and IL-18 induced acute thymic atrophy and expanded thymic neutrophils. Fate mapping using Ms4a3-Cre mice identified thymic granulocyte-monocyte progenitors (GMPs) as the source of these neutrophils, while Rag1-Cre tracing revealed a shared developmental lineage with lymphocytes.
Ex vivo neonatal thymic organ cultures (NTOCs) confirmed that TL1A and IL-18 synergistically enhance neutrophil production and egress. NOTCH inhibition with LY411575 further increased neutrophil numbers, indicating that NOTCH signaling restrains steady-state thymic granulopoiesis. Additionally, TL1A and IL-18 promoted myelopoiesis by elevating GM-CSF levels, primarily produced by thymic ILC1s. Notably, granulopoiesis was completely abrogated in Csf2rb-/- NTOCs and by GM-CSFR blockade, confirming GM-CSF as the critical driver of this process.
Overall, our findings reveal that TL1A and IL-18 synergistically induce acute thymic atrophy while driving extramedullary thymic granulopoiesis through a NOTCH- and GM-CSF-dependent mechanism.