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Germline gain-of-function (GOF) variants in STAT3 cause an inborn error of immunity associated with early-onset poly-autoimmunity and immune dysregulation. To study tissue-specific immune dysregulation, we used a mouse model carrying a missense variant (p.G421R) that causes human disease. We observed spontaneous and imiquimod (IMQ)-induced skin inflammation associated with cell-intrinsic local Th17 responses in STAT3 GOF mice. CD4+ T cells were sufficient to drive skin inflammation and showed increased Il22 expression in expanded clones. Certain aspects of disease, including increased epidermal thickness, also required the presence of STAT3 GOF in epithelial cells. Treatment with a JAK inhibitor improved skin disease without affecting local Th17 recruitment and cytokine production. These findings collectively support the involvement of Th17 responses in the development of organ-specific immune dysregulation in STAT3 GOF and suggest that the presence of STAT3 GOF in tissues is important for disease and can be targeted with JAK inhibition.

The mechanisms by which innate immune signals regulate alloimmune responses remain poorly understood. In the present study, we show by intravital 2-photon microscopy direct interactions between graft-infiltrating neutrophils and donor CD11c+dendritic cells (DCs) within orthotopic lung allografts immediately after reperfusion. Neutrophils isolated from the airways of lung transplantation recipients stimulate donor DCs in a contact-dependent fashion to augment their production of IL-12 and expand alloantigen-specific IFN-γ+T cells. DC IL-12 expression is largely regulated by degranulation and induced by TNF-α associated with the neutrophil plasma membrane. Extended cold ischemic graft storage enhances G-CSF–mediated granulopoiesis and neutrophil graft infiltration, resulting in exacerbation of ischemia-reperfusion injury after lung transplantation. Ischemia reperfusion injury prevents immunosuppression-mediated acceptance of mouse lung allografts unless G-CSF–mediated granulopoiesis is inhibited. Our findings identify granulopoiesis-mediated augmentation of alloimmunity as a novel link between innate and adaptive immune responses after organ transplantation.

The mechanisms by which innate immune signals regulate alloimmune responses remain poorly understood. In the present study, we show by intravital 2-photon microscopy direct interactions between graft-infiltrating neutrophils and donor CD11c+ dendritic cells (DCs) within orthotopic lung allografts immediately after reperfusion. Neutrophils isolated from the airways of lung transplantation recipients stimulate donor DCs in a contact-dependent fashion to augment their production of IL-12 and expand alloantigen-specific IFN-γ+ T cells. DC IL-12 expression is largely regulated by degranulation and induced by TNF-α associated with the neutrophil plasma membrane. Extended cold ischemic graft storage enhances G-CSF–mediated granulopoiesis and neutrophil graft infiltration, resulting in exacerbation of ischemia-reperfusion injury after lung transplantation. Ischemia reperfusion injury prevents immunosuppression-mediated acceptance of mouse lung allografts unless G-CSF–mediated granulopoiesis is inhibited. Our findings identify granulopoiesis-mediated augmentation of alloimmunity as a novel link between innate and adaptive immune responses after organ transplantation.

Unlike other tumors, lung cancer appears to be poorly sensitive to immunotherapy. We have recently demonstrated an alternative pathway of lung cancer immunosurveillance. Our data indicate a failure of the adaptive immune system to mediate the immunosurveillance of lung cancer and emphasize the prominent role of natural killer cells in this setting.