STING Gain-of-Function Disrupts Lymph Node Organogenesis and Innate Lymphoid Cell Development in Mice

Abstract

STING gain-of-function causes autoimmunity and immunodeficiency in mice and STING-associated vasculopathy with onset in infancy (SAVI) in humans. Here, we report that STING gain-of-function in mice prevents development of lymph nodes and Peyer's patches. We show that the absence of secondary lymphoid organs is associated with diminished numbers of innate lymphoid cells (ILCs), including lymphoid tissue inducer (LTi) cells. Although wild-type (WT) a4b7 + progenitors differentiate efficiently into LTi cells, STING gain-of-function progenitors do not. Furthermore, STING gain-of-function impairs development of all types of ILCs. Patients with STING gain-of-function mutations have fewer ILCs, although they still have lymph nodes. In mice, expression of the STING mutant in RORgT-positive lineages prevents development of lymph nodes and reduces numbers of LTi cells. RORgT lineage-specific expression of STING gain-of-function also causes lung disease. Since RORgT is expressed exclusively in LTi cells during fetal development, our findings suggest that STING gain-of-function prevents lymph node organogenesis by reducing LTi cell numbers in mice.

The cGAS–STING pathway as a therapeutic target in inflammatory diseases

“…Reduced numbers and anti-proliferative effects in T cells have also been observed in patients with SAVI, although these features are less prominent compared with what is seen in mice 48 , 114 . Notably, ablation of type I interferon signalling or disabling necroptosis had no effect on the disease pathogenesis in the N153S mouse model of SAVI, whereas depletion of T cells protected N153S mice from developing lung disease 120 , 122 – 124 . The extent to which the clinical manifestations seen in humans rely on type I interferon signalling or on T cell-mediated immunopathology is not yet clear.…”

The cGAS-STING Pathway: A Promising Immunotherapy Target

“…Subsequently, the impaired proliferation of T cells and other immune cells would cause severe innate and adaptive immunodeficiency to exacerbate the severity of SAVI. Recent studies have suggested that the reason for the T-cells deficiency caused by STING activation may be STING activation disrupt the calcium homeostasis or the migration of progenitors to the thymus ( 88 , 89 , 92 , 93 ). These findings suggested that STING was a critical factor in the occurrence and development of the SAVI via regulating the proliferation and differentiation of the T cells.…”

“…A representative example is that acquired mutations of the STING gene (STING N154S in humans and STING N153S in mice) cause STINGassociated vasculopathy with onset in infancy (SAVI), characterized by vasculopathy, ulcerative skin lesions, and pulmonary fibrosis, spontaneous colitis (86)(87)(88)(89)(90)(91). In the SAVI model, STING activation led to a cell-intrinsic T-cells defect (CD4 + and CD8 + T cells) via regulating the differentiation of progenitor cells and the lifespan of mature T cells (88,92). Subsequently, the impaired proliferation of T cells and other immune cells would cause severe innate and adaptive immunodeficiency to exacerbate the severity of SAVI.…”

Lung Inflammation in STING-Associated Vasculopathy with Onset in Infancy (SAVI)

“…Lung disease in the N153S mice appeared to be T-cellmediated, since Rag1 −/− STING N153S mice, which lack T cells and mature B cells, exhibited no histological evidence of lung disease and Tcrβ −/− STING N153S mice developed only very mild lung disease [60,61]. A disruption in the development of second lymphoid organs and, consequently, a reduction of innate lymphoid cells in mice were also demonstrated [62]. These results suggest a central role of hematopoietic-derived cells in the lung disease of N153S mice.…”