Activation of autoreactive lymphocytes in the lung by radioresistant cells expressing a STING gain-of-function mutation
Kevin MingJie Gao, Kristy Chiang, Sharon Subramanian, Xihui Yin, Paul J. Utz, Kerstin Nündel, Kate A. Fitzgerald, Ann Marshak-Rothstein
Kevin MingJie Gao, Kristy Chiang, Sharon Subramanian, Xihui Yin, Paul J. Utz, Kerstin Nündel, Kate A. Fitzgerald, Ann Marshak-Rothstein
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Research Article Inflammation

Activation of autoreactive lymphocytes in the lung by radioresistant cells expressing a STING gain-of-function mutation

Abstract

Gain-of-function mutations in the dsDNA sensing adaptor STING lead to a severe autoinflammatory syndrome known as STING-associated vasculopathy with onset in infancy (SAVI). Patients with SAVI develop interstitial lung disease (ILD) and produce autoantibodies that are commonly associated with systemic autoimmune diseases. Mice expressing the most common SAVI mutation, STING V154M (VM), similarly develop ILD but exhibit severe T and B cell lymphopenia and low serum Ig titers, and they lack autoantibodies. Importantly, lethally irradiated VM hosts reconstituted with WT stem cells (WT→VM) still develop ILD. In this study, we find that WT→VM chimeras had restored B cell function, produced autoantibodies, and thereby recapitulated the loss of tolerance seen in patients with SAVI. Lymphocytes derived from both WT and BCR or TCR transgenic (Tg) donors accumulated in the extravascular lung tissue of WT+Tg→VM mixed chimeras, but lymphocyte activation and germinal center formation required WT cells with a diverse repertoire. Furthermore, when T cells isolated from the WT→VM chimeras were adoptively transferred to naive Rag1-deficient secondary hosts, they trafficked to the lung and recruited neutrophils. Overall, these findings indicated that VM expression by radioresistant cells promoted the activation of autoreactive B cells and T cells that then differentiated into potentially pathogenic effector subsets.

Authors

Kevin MingJie Gao, Kristy Chiang, Sharon Subramanian, Xihui Yin, Paul J. Utz, Kerstin Nündel, Kate A. Fitzgerald, Ann Marshak-Rothstein

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Figure 3

Formation of GC B cells in VM lung requires an unrestricted repertoire.

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Formation of GC B cells in VM lung requires an unrestricted repertoire. ...
(A) Six-week-old age- and sex-matched CD45.1/CD45.1 WT and VM littermates were lethally irradiated and reconstituted with a mixture of BM stem cells comprised of 20% CD45.1/CD45.2 WT and 80% CD45.2/CD45.2 MD4 Rag1–/– cells. WT+MD4→WT (n = 4–8) and WT+MD4→VM (n = 6–9) chimeric mice were then evaluated 8–9 weeks later. (B) Percentage of MD4 donor–derived cells within all CD45+ cells in BM, BM B220+ B cells, or splenic CD19+ B cells, or within the lung extravascular (EV) B cells of either the WT hosts (gray bar) or VM hosts (red bar), after excluding any CD45.1 single-positive radio-resistant host cells. (C) Total number of lung EV B cells derived from either the WT or MD4 donor in either the WT or VM hosts. (D–G) Percentage of IgD+ naive B cell, IgD– Fas+ GL7+ germinal center (GC) B cells, B220– CD138+ PC cells, and IgD– Fas+ GL7– B cells derived from either the WT or MD4 donor within the EV B cell compartment of either WT or VM host. (H–K) Percentage of naive B cells, GC B cells, PCs, and IgD–Fas+GL7– B cells derived from WT or MD4 donor within the splenic B compartment of WT or VM hosts. For C–K, data points in columns 1 and 2 represent paired WT and MD4 donors from a shared WT host. Similarly, data points in columns 3 and 4 represent paired WT and MD4 donors from a shared VM host. To determine statistical significance, nonparametric Mann-Whitney U tests were used for pair-wise comparisons between columns 1 and 3 and between columns 2 and 4. A Wilcoxon matched pairs signed rank test was used for pairwise comparisons between columns 3 and 4 (*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001).