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RNA-seq of BATF-overexpressing CD8 T cells in vitro

ABSTRACT: T cells infiltrate pancreatic islets during the progression of type 1 diabetes (T1D) but their differentiation states have not been completely defined. We used unbiased single-cell RNA sequencing analyses to gain further insight into the phenotypic complexity of islet-infiltrating T cells in non-obese diabetic (NOD) mice. In the CD4 T cell compartment, we identified naïve, memory, and regulatory T cells, as well as multiple Il21 expressing effector subsets positive for markers indicative of Th1 and Tfh cells. In CD8 T cells, we identified two activated subsets in addition to naïve cells. The two activated islet CD8 T cell subsets respectively resemble the self-renewing progenitor cells and the terminally differentiated/exhausted effectors during chronic lymphocytic choriomeningitis virus infection. We also identified a BATF-driven transcriptional signature promoting the diabetogenic activity of islet-infiltrating β cell autoreactive CD8 T effectors. Our results provide a useful resource for understanding T cell differentiation programs in T1D.

ORGANISM(S): Mus musculus

PROVIDER: GSE125452 | GEO | 2024/01/22

REPOSITORIES: GEO

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Project description:Like humans, the NOD mouse and other diabetes susceptible rat strains, T1D in BB rats is dependent on the major histocompatibility complex (MHC, insulin dependent diabetes mellitus locus 1, Iddm1) located on chromosome 20. In rats this is the HLA-DQB1 homologue RT1-B, specifically the RT1u haplotype. Our studies employ congenic derivatives of the BB rat, the DRlyp/lyp and DR+/+ strains, which differ only by the 2 Mb lyp (lymphopenia, Iddm2) region on chromosome 4. TID in the lymphopenic DRlyp/lyp rat is spontaneous and onset occurs in 100% of animals during adolescence (65.3+/-6.3 days) due to a recessive mutation within GIMAP5 (GTPase, IMAP family member 5). Gimap5 is a mitochondrial GTP-binding protein necessary for post-thymic T cell survival. The spontaneously diabetic phenotype observed in DRlyp/lyp rats is thought to be elicited through deficiency in CD4+CD25+ TREG cells as T1D in lymphopenic BB rats can be rescued through adoptive transfer of this population. Genetic variation in GIMAP5 has been associated with the development of protein-tyrosine phosphatase-2 (IA-2) autoantibodies in human T1D [28] and is significantly associated with systemic lupus erythematosus (SLE). The non-lymphopenic DR+/+ strain possesses wild-type GIMAP5 alleles and does not develop spontaneous T1D, however, T1D is inducible through administration of lymphotoxic anti-RT6 monoclonal antibody and immune activating polyinosinic polycytidylic acid (poly I:C; a ligand of toll-like receptor 3), or through viral depletion of CD4+CD25+ regulatory T (TREG) cells. Such treatments do not induce T1D in the related Wistar-Furth (WF) rats and suggest the presence of an underlying diabetic predisposition in BB rats that is phenotypically manifested upon loss of immune regulation. DRlyp/lyp and DR+/+ rats possess characteristics that make them ideal for the identification of pathways relevant to the development of T1D since they possess absolute or conditional susceptibility to T1D. The Gimap-/- Iddm2 locus conveys upon DRlyp/lyp rats a deficiency in immune regulatory capacity and the spontaneous T1D phenotype. Consistent with the concept that autoimmunity involves both a lack of self-tolerance as well as target organ-specific factors, we have discovered that DRlyp/lyp and DR+/+ (BB) rats share an islet specific stress. This is reflected by the expression of immune mediators, including the chemokine eotaxin that recruits eosinophils, certain T cell subsets, dendritic cells, and mast cells, by islet Î² cells early in life, before infiltration of immune cells into the islet (insulitis). While BB and WF rats share Iddm1 (RT1u/u MHC), islet eotaxin expression in not observed in WF islets and thus is associated with the T1D susceptibility of BB rats. Further supporting the hypothesis that additional genetic factors, perhaps those working at the level of the pancreatic Î² cell, are necessary for the development of T1D are the observations that 1) The generation Fischer 344 (F344) rats either homozygous for Gimap5-/- or homozygous for both RT1u/u and Gimap5-/- fail to develop T1D; and 2) genetic crosses between BB rats and non diabetic strains have identified numerous Iddm loci independent of Iddm1 and Iddm2. In this study, using islet gene expression profiling, direct serum-level measurement, quantitative real-time PCR and targeted histological follow-up, we investigate pancreatic islet gene expression in BB rat at 5 weeks (+/-5 days) which is prior to insulitis in DRlyp/lyp rats. We compare DR+/+, JB++, JBlyp/lyp and DRlyp/lyp islet activity to that of WF and F344 rats to investigate any potential for reduction in capability to deal with oxidative stress in BB rats compared to non-BB and whether any differences in that capability map to known Iddm regions.

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RNA-seq of BATF-overexpressing CD8 T cells in vitro

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