CD30 plays a role in T-dependent immune response and T cell proliferation.

CD30 is a member of the tumor necrosis factor receptor (TNFR) superfamily and expressed in both normal and malignant lymphoid cells. However, the role of CD30 in lymphopoiesis is not known. In this study, we showed CD30 was expressed both in T and B cells, but its deficiency in mice had no effect on T- and B-cell development. In fact, CD30 deficiency attenuated B-cell response to T-cell-dependent antigens. The impaired B cell response in CD30-deficient mice is caused by the reduction of activation-induced cytidine deaminase (AID) expression. Moreover, CD30-deficient mice exhibited decreased TCR-mediated T cell proliferation and slightly impaired TCR signaling. High-throughput RNA sequencing analysis revealed that CD30 deficiency led to a decrease of FOXO-autophagy axis in T cells upon TCR stimulation. Thus, CD30 positively regulates T-cell-dependent immune response and T cell proliferation.

cGAS activation causes lupus-like autoimmune disorders in a TREX1 mutant mouse model.

TREX1 encodes a major cellular DNA exonuclease. Mutations of this gene in human cause cellular accumulation of DNA that triggers autoimmune diseases including Aicardi-Goutieres Syndrome (AGS) and systemic lupus erythematosus (SLE). We created a lupus mouse model by engineering a D18 N mutation in the Trex1 gene which inactivates the enzyme and has been found in human patients with lupus-like disorders. The Trex1D18N/D18N mice exhibited systemic inflammation that consistently recapitulates many characteristics of human AGS and SLE. Importantly, ablation of cGas gene in the Trex1D18N/D18N mice rescued the lethality and all detectable pathological phenotypes, including multi-organ inflammation, interferon stimulated gene induction, autoantibody production and aberrant T-cell activation. These results indicate that cGAS is a key mediator in the autoimmune disease associated with defective TREX1 function, providing additional insights into disease pathogenesis and guidance to the development of therapeutics for human systemic autoimmune disorders.

Suppression of TREX1 deficiency-induced cellular senescence and interferonopathies by inhibition of DNA damage response.

TREX1 encodes a major DNA exonuclease and mutations of this gene are associated with type I interferonopathies in human. Mice with Trex1 deletion or mutation have shortened life spans accompanied by a senescence-associated secretory phenotype. However, the contribution of cellular senescence in TREX1 deficiency-induced type I interferonopathies remains unknown. We found that features of cellular senescence present in Trex1-/- mice are induced by multiple factors, particularly DNA damage. The cGAS-STING and DNA damage response pathways are required for maintaining TREX1 deletion-induced cellular senescence. Inhibition of the DNA damage response, such as with Checkpoint kinase 2 (CHK2) inhibitor, partially alleviated progression of type I interferonopathies and lupus-like features in the mice. These data provide insights into the initiation and development of type I interferonopathies and lupus-like diseases, and may help inform the development of targeted therapeutics.

DWL-4-140: A allene small molecule targeting STING that alleviates lupus-like phenotype in Trex1-/- mice.

The innate immune system plays a critical role in the host response against pathogenic microbial infection. However, aberrant activation of the innate immune pathways is a characteristic feature of various diseases. Thus, targeted drugs must be developed based on the understanding of the innate immune signaling pathways. This study demonstrated that an allene small molecule (DWL-4-140) can efficiently and selectively exert regulatory effects on the stimulator of interferon genes (STING), resulting in the downregulation of DNA-induced interferon responses. Mechanistically, DWL-4-140 targeted the cyclized nucleotide-binding domain (CBD) of STING, inhibiting the assembly of the STING multimeric complex and the recruitment of downstream signaling mediators. In addition to downregulating the 10-carboxymethyl-9-acridanone-induced production of inflammatory factors, DWL-4-140 alleviated the pathological features of Trex1 deletion-induced lupus in mice. Thus, this study demonstrated that DWL-4-140 pharmacologically inhibits STING with potential therapeutic applications in auto-inflammatory diseases.

Cyclic dinucleotides mediate bacterial immunity by dinucleotide cyclase in Vibrio.

The cyclic GMP-AMP (cGAMP) synthase (cGAS) recognizes cytosolic DNA and synthesizes the second messenger, cGAMP, thus activating the adaptor protein stimulator of interferon genes (STING) and initiating the innate immune responses against microbial infections. cGAS-STING pathway has been crucially implicated in autoimmune diseases, cellular senescence, and cancer immunotherapy, while the cGAS-like receptors in bacteria can protect it against viral infections. Dinucleotide cyclase in Vibrio (DncV) is a dinucleotide cyclase originally identified in Vibrio cholerae. The synthesis of cyclic nucleotides by DncV, including c-di-GMP, c-di-AMP, and cGAMP mediates bacterial colonization, cell membrane formation, and virulence. DncV is a structural and functional homolog of the mammalian cytoplasmic DNA sensor, cGAS, implicating cGAS-STING signaling cascades may have originated in the bacterial immune system. Herein, we summarize the roles of DncV in bacterial immunity, which are expected to provide insights into the evolution of cGAS-STING signaling.

Celastrol ameliorates autoimmune disorders in Trex1-deficient mice.

Celastrol is one of most potent bioactive molecule isolated from the medicinal plant Tripterygium wilfordii (Thunder God Vine) and is well known for its potential therapeutic value against various chronic diseases including the autoimmune diseases, such as systemic lupus erythematosus and Aicardi-Goutieres syndrome, or other interferonopathies. However, the underlying mechanism of celastrol function remains unclear. Here we showed that celastrol caused inhibition of interferon regulatory factor 3 (IRF3) activation leading to the down-regulation of the interferon response triggered by cytosolic nucleic acids in vitro and in vivo. Moreover, celastrol treatment markedly ameliorates the autoimmune phenotypes including myocarditis, aberrant interferon response and autoantibody production, as well as the excessive T-cell activation in Trex1-/- autoimmune disease mouse model. Collectively, our results indicate that celastrol inhibits interferon response by targeting IRF3 activation and may be used as an effective treatment for interferon response-dependent autoimmune diseases.