Ji, P.; Ren, K.; Han, X.; Li, E.; Wang, P.; Bi, H.; Cai, W.; Aydemir, I.; Wai, C. M.; Niu, H.; Yang, J.; Liu, Y.; Vadasz, B.; Sukhanova, M.; Fang, D.; Cui, W.

An inflammatory bone marrow microenvironment is increasingly recognized as critical in myeloid disease evolution, yet how stromal inflammation interfaces with adaptive immunity remains poorly defined. Here, we show that stromal pyroptosis drives mutation-specific myeloid expansion by coordinating monocytic remodeling and CD4 T-cell activation. Genetic ablation of gasdermin D in the bone marrow stroma suppressed stromal pyroptosis and attenuated Tet2-deficient myeloid expansion. Tet2 deficiency skewed monocyte and macrophage differentiation toward an activated, antigen-presenting state that interacted with pyroptotic stromal cells to promote expansion of a distinct CD4 T-cell population. These cells expressed canonical T follicular helper markers (Bcl6, Cxcr5, Il21, and Cd40l) together with interferon-responsive and tissue-interaction programs, consistent with an inflammation-adapted TFH-like state. CD40L produced by these cells reinforced the expansion of Tet2-deficient monocytes and macrophages, establishing a feed-forward stromal-immune circuit. Disruption of this axis through stromal gasdermin D deficiency or CD40L blockade attenuated myeloid expansion in vivo. Consistent with these findings, patients with isolated TET2 loss-of-function mutations exhibited CD4 T-cell skewing and CD40L+ T-cell-rich tertiary lymphoid structures in the bone marrow. Together, these data identify a pyroptosis-dependent stromal-immune axis that links early myeloid inflammation to maladaptive remodeling of adaptive immunity and reveals a context-dependent therapeutic vulnerability in Tet2-deficient hematopoiesis.