Activated STING in the thymic epithelium alters T cell development and selection leading to autoimmunity
Zimu Deng, Christopher S. Law, Santosh Kurra, Noa Simchoni, Anthony K. Shum
Zimu Deng, Christopher S. Law, Santosh Kurra, Noa Simchoni, Anthony K. Shum
View: Text | PDF
Research Article Autoimmunity Immunology

Activated STING in the thymic epithelium alters T cell development and selection leading to autoimmunity

Abstract

Coatomer protein complex subunit α (COPA) syndrome is a monogenic disorder of immune dysregulation that leads to interstitial lung disease and high-titer autoantibodies. Constitutive activation of the innate immune molecule stimulator of interferon genes (STING) is centrally involved in disease. However, the mechanisms by which STING results in autoimmunity are not well understood in COPA syndrome and other STING-associated diseases. Prior studies showed a cell autonomous role for STING in thymocyte development. Single-cell data of human thymus demonstrated that STING is highly expressed in medullary thymic epithelial cells (mTECs) and at levels much greater than in T cells. Here, we show that in certain contexts, activated STING exerts a functional role in the thymic epithelium to alter thymocyte selection and predisposes to autoimmunity. In CopaE241K/+ mice, activated STING in mTECs amplified IFN signaling, impaired macroautophagy, and caused a defect in negative selection of T cell precursors. WT mice given a systemic STING agonist phenocopied the selection defect and showed enhanced thymic escape of a T cell clone targeting a self-antigen also expressed in melanoma. Our work demonstrates that STING activation in TECs shapes the T cell repertoire and contributes to autoimmunity, findings that are important for conditions that activate thymic STING.

Authors

Zimu Deng, Christopher S. Law, Santosh Kurra, Noa Simchoni, Anthony K. Shum

×

Figure 5

A systemic STING agonist increases autoreactive T cells in the thymus.

Options: View larger image (or click on image) Download as PowerPoint
A systemic STING agonist increases autoreactive T cells in the thymus. (...
(A) Left: CD4+ and CD8+ profile of thymocytes and CD3+ and Vβ14+ expression of CD4+ SP thymocytes in Rag1–/– Tyrp1B-w/wt TCR mice treated with diABZI STING agonist or vehicle. Right: change in percentage of total thymic CD4+ SP and Vβ14+CD4+ SP following STING agonist treatment (vehicle, n = 14; agonist, n = 21; compiled from 3 independent experiments). (B) Left: cleaved caspase 3 on CD5hi TCRβhi thymocytes in vehicle- and agonist-treated mice. Right: percentage of thymocytes undergoing clonal deletion in agonist-treated mice relative to vehicle treatment (vehicle, n = 13; agonist, n = 14; compiled from 3 independent experiments). Unpaired, parametric, 2-tailed Student’s t test was used for statistical analysis. (C) Left: flow analysis of splenic CD4+ SP Vβ14+ autoreactive T cells in vehicle- and agonist-treated mice. Right: absolute number of CD4+ SP Vβ14+ autoreactive T cells. (D) Absolute number of splenic and inguinal CD4+ SP and Vβ14+ autoreactive T cells in vehicle- and agonist-treated mice (vehicle, n = 14; agonist, n = 21; 3 independent experiments). LN, lymph node. (E) B16 melanoma growth in Rag1–/– mice that received x-ray radiation, PD-1 antibody, and adoptively transferred splenocytes from Rag1–/– Tyrp1B-w/wt TCR mice treated with STING agonist (n = 5) or vehicle (n = 4) (data represent 3 independent experiments). Locally estimated scatter plot smoothing with 95% confidence interval of B16 tumor growth over time. (F) Quantitation of CD3+ CD45.1 donor cells within the periphery after transfer into CD45.2 host and treatment with agonist (n = 8) or vehicle (n = 9). Data were pooled from 3 independent experiments. (G) Mean expression of STING1 transcript in select cell types in human thymus. Data are mean ± SD. Two-tailed Mann-Whitney U test was used for statistical analysis unless indicated above. A P value of less than 0.05 was considered statistically significant.