Concannon, P. J. | bioRxiv Science

bioRxiv2024

Reduced function of the adaptor SH2B3 promotes T1D via altered γc cytokine-regulated, T cell intrinsic immune tolerance

Genome-wide association studies have identified SH2B3 as an important non-MHC gene for islet autoimmunity and type 1 diabetes (T1D). In this study, we found a single SH2B3 haplotype significantly associated with increased risk for human T1D, and this haplotype carries the single nucleotide variant rs3184504*T in SH2B3. To better characterize the role of SH2B3 in T1D, we used mouse modeling and found a T cell-intrinsic role for SH2B3 regulating peripheral tolerance. SH2B3 deficiency had minimal effect on TCR signaling or proliferation across antigen doses, yet enhanced cell survival and cytokine signaling including common gamma chain-dependent and interferon-gamma receptor signaling. SH2B3 deficient CD8+T cells showed augmented STAT5-MYC and effector-related gene expression partially reversed with blocking autocrine IL-2 in culture. Using the RIP-mOVA model, we found CD8+ T cells lacking SH2B3 promoted early islet destruction and diabetes without requiring CD4+ T cell help. SH2B3-deficient cells demonstrated increased survival post-transfer compared to control cells despite a similar proliferation profile in the same host. Next, we created a spontaneous NOD.Sh2b3-/-mouse model and found markedly increased incidence and accelerated T1D across sexes. Collectively, these studies identify SH2B3 as a critical mediator of peripheral T cell tolerance limiting the T cell response to self-antigens. Article HighlightsO_LIThe rs3184504 polymorphism, encoding a hypomorphic variant of the negative regulator SH2B3, strongly associates with T1D. C_LIO_LISH2B3 deficiency results in hypersensitivity to cytokines, including IL-2, in murine CD4+ and CD8+ T cells. C_LIO_LISH2B3 deficient CD8+ T cells exhibit a comparable transcriptome to wild-type CD8+ T cells at baseline, but upon antigen stimulation SH2B3 deficient cells upregulate genes characteristic of enhanced JAK/STAT signaling and effector functions. C_LIO_LIWe found a T-cell intrinsic role of SH2B3 leading to severe islet destruction in an adoptive transfer murine T1D model, while global SH2B3 deficiency accelerated spontaneous NOD diabetes across sexes. C_LI

immunology↗

bioRxiv2023

Multi-omics profiling reveals ethylene signalling as a key pathway underlying both genetic and epigenetic responses to low-dose ionizing radiation in Arabidopsis

There is increasing interest in the effects of low-dose ionizing radiation (IR) on plants as might occur during spaceflight, or as a consequence of human activities, such as nuclear power generation, that may result in the release of radioactive materials into the environment. High IR doses have long been used for the induction of mutations in plants with the goal of generating desirable traits for agribusiness. Less is known about the responses of plants to acute low doses of IR exposure. Here, we take a multi-omics approach to characterize the response to low dose IR in Arabidopsis thaliana. We adapt the Methyltransferase Accessibility Protocol for individual templates (MAPit) technique for use in plants allowing us to assay the epigenetic response to acute low-dose IR (10 cGy and 100 cGy) 72 hr after exposure, and, in parallel, use RNA sequencing to profile the transcription response at 1, 3, 24 and 72 hr after exposure. IR exposures as low as 10 cGy elicit robust genetic responses in A. thaliana detectable as early as 1 hr after exposure. Further examination revealed dose-dependent changes in gene expression, chromatin accessibility and DNA methylation that implicate the ethylene signalling pathway and abiotic stress response as underlying the transcriptional and epigenetic changes associated with IR. These changes are observable up to 72 hr post-exposure, suggesting that they are maintained well after the initial acute exposure. Our findings indicate that A. thaliana executes a multi-modal response to low-dose IR through induction and regulation of the ethylene response pathway.

genomics↗