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Reduced CD8 T cell exhaustion in DR4 risk subjects is selectively augmented with therapy [CD8s]

ABSTRACT: Exhausted CD8 T cells (TEX) are associated with worse outcome in cancer yet better outcome in autoimmunity. However, factors contributing to reduced TEX in autoimmunity are poorly understood. We use two genetically related autoimmune diseases, type 1 diabetes (T1D) and rheumatoid arthritis (RA), to explore these factors. We identify a common human peripheral blood TIGIT+KLRG1+ CD8 TEX population: TIGIT+KLRG1+ CD8 TEX of healthy controls (HC), T1D, and rheumatoid arthritis (RA) subjects share EOMES signature genes, are increased with age and in chronic viral-specific cells and are hyporesponsive in vitro. Consistent with a genetic determinant, TIGIT+KLRG1+ TEX are stable within but vary between individuals. In HC and RA subjects (n>100/cohort), lower levels of EOMES transcriptional modules and TIGIT+KLRG1+ TEX were associated with RA HLA risk alleles (DR0401, 0404, 0405, 0408, 1001) even when considering disease status and CMV seropositivity. TIGIT+KLRG1+ TEX significantly increased in RA HLA risk but not non-risk subjects treated with abatacept (CTLA4Ig); no change in TIGIT+KLRG1+ TEX was observed with adalimumab (anti-TNF) therapy. The DR4 association and selective modulation with abatacept suggests that therapeutic modulation of TEX may be more effective in DR4 subjects and TEX may be indirectly influenced by cellular interactions that are blocked by abatacept.

ORGANISM(S): Homo sapiens

PROVIDER: GSE216679 | GEO | 2023/06/30

REPOSITORIES: GEO

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Reduced CD8 T cell exhaustion in DR4 risk subjects is selectively augmented with therapy [whole blood]

Project description:Exhausted CD8 T cells (TEX) are associated with worse outcome in cancer yet better outcome in autoimmunity. However, factors contributing to reduced TEX in autoimmunity are poorly understood. We use two genetically related autoimmune diseases, type 1 diabetes (T1D) and rheumatoid arthritis (RA), to explore these factors. We identify a common human peripheral blood TIGIT+KLRG1+ CD8 TEX population: TIGIT+KLRG1+ CD8 TEX of healthy controls (HC), T1D, and rheumatoid arthritis (RA) subjects share EOMES signature genes, are increased with age and in chronic viral-specific cells and are hyporesponsive in vitro. Consistent with a genetic determinant, TIGIT+KLRG1+ TEX are stable within but vary between individuals. In HC and RA subjects (n>100/cohort), lower levels of EOMES transcriptional modules and TIGIT+KLRG1+ TEX were associated with RA HLA risk alleles (DR0401, 0404, 0405, 0408, 1001) even when considering disease status and CMV seropositivity. TIGIT+KLRG1+ TEX significantly increased in RA HLA risk but not non-risk subjects treated with abatacept (CTLA4Ig); no change in TIGIT+KLRG1+ TEX was observed with adalimumab (anti-TNF) therapy. The DR4 association and selective modulation with abatacept suggests that therapeutic modulation of TEX may be more effective in DR4 subjects and TEX may be indirectly influenced by cellular interactions that are blocked by abatacept.

2023-06-30 | GSE216678 | GEO

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Genome-wide DNA methylation profiling of CD4+ T cells and CD19+ B cells in autoimmune-disease associated HLA class II genotype carriers (HLA-DR2-DQ6, -DR3-DQ2 and -DR4-DQ8 homozygotes) using Illumina Infinium HumanMethylation EPIC beadchip

Project description:The Human leukocyte antigen (HLA) -region, especially HLA class I and II genes, plays a major role in the predisposition to autoimmune disorders. Particularly three HLA haplotypes, DRB1*03-DQA1*05-DQB1*02 (DR3-DQ2), DRB1*04:01-DQA1*03-DQB1*03:02 (DR4-DQ8) and DRB1*15-DQA1*01-DQB1*06:02 (DR2-DQ6), have an important role in many autoimmune diseases: for example, in type 1 diabetes (T1D) the DR2-DQ6 is associated with a strongly decreased T1D risk and the DR3-DQ2 and DR4-DQ8 are associated with a moderately increased T1D risk. To clarify the mechanisms behind this association, we examined genome-wide DNA methylation in CD4+ T cells and CD19+ B cells of healthy subjects homozygous either for DR3-DQ2 (n = 19), DR4-DQ8 (n = 17) or DR2-DQ6 (n = 14), and compared methylation between the genotypes. For the study, CD4+ T cells and CD19+ B cells were isolated consecutively from PBMC samples using magnetic bead separation. DNA was extracted from the cell lysates with AllPrep DNA/RNA/miRNA Universal Kit (Qiagen, Germany). Then the individual DNA samples were pooled into 11 pooled samples with 4–5 samples per pooled sample. The original 50 samples were designated pools based on age and sex to ensure that the age and sex distributions would be as similar as possible between the pooled samples. The mean age (±SD) in the three HLA-groups (DR2-DQ6, DR3-DQ2 and DR4-DQ8) were 15.0 (±8.3), 11.1 (±5.6) and 11.8 (±7.9) and their male to female ratios were 8/6, 9/10 and 11/6. Similar pooled samples were created for both the CD4+ T cell and the CD19+ B cell samples. Then DNA methylation was examined in the pooled CD4+ T cell and CD19+ B cell samples using Illumina Infinium HumanMethylation EPIC beadchip.

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2017-05-17 | E-GEOD-68215 | biostudies-arrayexpress

TCR sequencing analysis of islets from NOD mice on hydrolyzed casein and hydrolyzed casein + 4% gluten diets

Project description:Protein source in diet greatly influences the incidence of type-1 diabetes (T1D) in non-obese diabetic (NOD) mouse colonies. NOD mice fed a diet containing hydrolyzed casein (HC) as the sole protein source are protected from T1D. Replacing 1/5th of the HC with gluten restores high T1D to NOD mice. We hypothesized that gluten might promote inflammation in the islets. We used TCR sequencing to characterize the clonal frequency of infiltrating T cells from the pancreatic islets of Langerhans of NOD mice fed a 20% HC diet or a 16% HC + 4% gluten diet.

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Gene expression profiling in Abatacept treated Rheumatoid Arthritis patients according to response

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Transcriptional Signatures as a Disease-Specific and Predictive Inflammatory Biomarker for Type 1 Diabetes [T1D_114]

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2012-09-01 | E-GEOD-35725 | biostudies-arrayexpress

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Project description:Protein source in diet greatly influences the incidence of type-1 diabetes (T1D) in non-obese diabetic (NOD) mouse colonies. NOD mice fed a diet containing hydrolyzed casein (HC) as the sole protein source are protected from T1D. Replacing 1/5th of the HC with gluten restores high T1D to NOD mice. We hypothesized that gluten might promote inflammation in the islets. We used single cell RNA sequencing (scRNAseq) to characterize and contrast the transcriptional profiles of endocrine cells and islet infiltrating leukocytes from the pancreatic islets of Langerhans of NOD mice fed a 20% HC diet or a 16% HC + 4% gluten diet.

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