Reduced function of the adaptor SH2B3 promotes T1D via altered gc cytokine-regulated, T cell intrinsic immune tolerance.
Taylor K WatsonAaron B I RosenTravis DrowJacob A MedjoMatthew A MacQuiveyYan GeH Denny LiggittDane A GrosvenorKimberly A Dill-McFarlandMatthew C AltmanPatrick J ConcannonJane H BucknerDavid J RawlingsEric J AllenspachPublished in: bioRxiv : the preprint server for biology (2024)
The rs3184504 polymorphism, encoding a hypomorphic variant of the negative regulator SH2B3, strongly associates with T1D.SH2B3 deficiency results in hypersensitivity to cytokines, including IL-2, in murine CD4+ and CD8+ T cells.SH2B3 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.We 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.
Keyphrases
- wild type
- type diabetes
- cardiovascular disease
- induced apoptosis
- transcription factor
- gene expression
- cell death
- single cell
- rna seq
- oxidative stress
- immune response
- mesenchymal stem cells
- cell proliferation
- early onset
- skeletal muscle
- bone marrow
- drug induced
- endoplasmic reticulum stress
- cell cycle arrest
- replacement therapy