Trending topics and news in HCT and Cellular Therapy

NLRP6 Regulates Donor T Cell Activation and Acute Graft-Versus-Host Disease Via ZAP-70-Erk Pathway

NLRP6 expressed in recipient intestinal epithelial cells is known to worsen gastrointestinal acute graft-versus-host disease (aGVHD), but its function within donor T cells has been undefined. Work published in Haematologica, led by Yamagata University with collaborators in Japan, Germany, and the United States, shows that NLRP6 acts as an intrinsic brake on donor T-cell activation. Loss of NLRP6 in donor T cells intensified aGVHD through enhanced ZAP-70–ERK signaling, T-cell proliferation, and inflammatory Th1 responses, without compromising graft-versus-tumor activity.

Donor T cells drive aGVHD after allogeneic hematopoietic cell transplantation (HCT) but are also required for the potentially curative graft-versus-tumor effect, so interventions capable of separating the two are of particular interest. The authors compared wild-type and Nlrp6-deficient donor T cells across four murine transplant models: major histocompatibility complex-mismatched, haploidentical, minor antigen-mismatched, and conditioning-free. Patient samples were examined to determine whether NLRP6 expression differs during clinical aGVHD.

Recipients of Nlrp6-deficient donor T cells had significantly poorer survival and more severe aGVHD than those receiving wild-type cells, and the result was reproduced independently in laboratories in Japan and the United States. The increased disease was mediated primarily by CD4-positive rather than CD8-positive donor T cells and occurred even without conditioning-related tissue damage. Nlrp6-deficient T cells displayed greater proliferation, DNA synthesis, IFN-γ production, T-bet expression, and Th1 differentiation, alongside increased apoptosis and exhaustion markers. Mechanistically, loss of NLRP6 increased phosphorylation of ZAP-70 and ERK1/2 after T-cell receptor stimulation, while Lck and STAT3 signaling remained unchanged. Tumor-related mortality did not increase, cytotoxic function was preserved, and early tumor clearance was modestly improved. NLRP6 expression was significantly lower in CD4- and CD8-positive T cells from patients with aGVHD than from healthy controls. These findings indicate that NLRP6 has cell-specific effects during transplantation and may represent a therapeutic target for separating harmful GVHD responses from beneficial antitumor immunity.

Reference:

Matsuki E, Miyata M, Sato R, et al. NLRP6 regulates donor T cell activation and acute graft-versus-host disease via ZAP-70-Erk pathway. Haematologica. Published online July 2, 2026. https://doi.org/10.3324/haematol.2025.289144