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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

An Atlas of Immune Cell Exhaustion in HIV-Infected Individuals Revealed by Single-Cell Transcriptomics

Project description:We investigated the effects of HIV infection on immune cell exhaustion at the transcriptomic level by analyzing single-cell RNA sequencing of peripheral blood mononuclear cells from four healthy subjects (37,847 cells) and six HIV-infected donors (28,610 cells). We identified nine immune cell clusters and eight T cell subclusters according to their unique gene expression programs; three of these (exhausted CD4+ and CD8+ T cells and interferon-responsive CD8+ T cells) were detected only in samples from HIV-infected donors. An inhibitory receptor KLRG1 was identified in the exhausted T cell populations and further characterized in HIV infected individuals. We identified a HIV-1 specific exhausted CD8+ T cell population expressing KLRG1, TIGIT, and T-betdimEomeshi markers. Ex-vivo antibody blockade of KLRG1 restored the function of HIV-specific exhausted CD8+ T cells demonstrating the contribution of KLRG1+ population to T cell exhaustion and providing an immunotherapy target to treat HIV chronic infection. Analysis of gene signatures also revealed impairment of B cell and NK cell function in HIV-infected donors. These data provide a comprehensive analysis of gene signatures associated with immune cell exhaustion during HIV infection, which could be useful in understanding exhaustion mechanisms and developing new cure therapies.

2020-09-12 | GSE157829 | GEO

B lymphocyte alterations accompany abatacept resistance in new-onset type 1 diabetes

Project description:Peripheral blood samples were collected from subjects enrolled in the TrialNet study TN-09. This was a phase II study of the effects of the T cell costimulation inhibitor CTLA4-Ig (abatacept) in new-onset T1D. Total RNA was isolated from whole blood samples and then globin-reduced. RNAseq libraries were prepared from the globin-reduced RNA.

2019-02-28 | GSE124284 | GEO

A comparison of the transcriptional profiles of invariant NKT cells derived from Wild type and Eomes conditional knockout mice

Project description:Functional subsets of iNKT cells, NKT1, NKT2 and NKT17, have been reported to arise during the thymus to peripheral differentiation stages. The key transcription factors for NKT1, NKT2 and NKT17 development in the thymus have been identified as T-bet, Gata3 and Rorγt, respectively. In contrast, these iNKT cell subsets can also undergo further differentiation in the periphery. Eomesodermin (Eomes) is a T-box transcription factor with high homology to T-bet and is expressed by activated CD8+ T cells as well as in resting and activated NK cells. However, its role in invariant (i)NKT cells remains unknown. Here, we show the impact of Eomes on iNKT cells in the thymus and peripheral tissue using conditional knockout (Eomes-cKO) mice. Eomes regulates the differentiation of NKT1 cells in the thymus. In the peripheral tissue, Klrg1+ iNKT1 cells are generated in lung after vaccination with -GalCer-pulsed DCs (DC/Gal) as memory like iNKT cells. In the current study, we found that Eomes also regulates their differentiation into memory-like KLRG1+iNKT cells in the periphery.

2019-05-09 | GSE128069 | GEO

Interconnected lineage trajectories link conventional and NK-like exhausted CD8+ T cells beneficial in T1D [P452_3]

Project description:While distinct NK-like CD57+ and PD-1+ CD8+ exhausted T cell populations (Tex) were both linked to beneficial immunotherapy response in autoimmune Type 1 Diabetes (T1D) patients, relationships between these cell types are poorly understood. We show that PD-1+ and CD57+ Tex populations in this context were epigenetically similar, but CD57+ Tex cells displayed unique increased chromatin accessibility of inhibitory Killer Cell Immunoglobulin-like Receptor (iKIR) and other NK cell genes. PD-1+ and CD57+ Tex also showed reciprocal expression of Inhibitory Receptors (IRs) and iKIRs accompanied by chromatin accessibility of Tcf1 and Tbet transcription factor target sites, respectively. CD57+ Tex showed unappreciated gene expression heterogeneity and shared clonal relationships with PD-1+ Tex, with these cells differentiating along four interconnected lineage trajectories: Tex-PD-1+, Tex-CD57+, Tex-Branching, and Tex-Fluid. Our findings demonstrate new relationships between Tex populations in human autoimmune disease and suggest that modulating common precursor populations may enhance response to autoimmune disease treatment.

2024-01-17 | GSE237613 | GEO

Interconnected lineage trajectories link conventional and NK-like exhausted CD8+ T cells beneficial in T1D [P362-1]

2024-01-17 | GSE237611 | GEO

Distinct exhausted CD8 T cell populations are linked to C-peptide preservation in alefacept-treated, recent onset T1D subjects

Project description:Bulk RNA-sequencing of sorted CD8 T cells from recent-onset T1D subjects treated with alefacept.

2020-12-10 | GSE158292 | GEO

Exhausted-like CD8 T cell phenotypes linked to C-peptide preservation in alefacept-treated T1D subjects - sorted CD8 subsets

Project description:Bulk RNA-sequencing of sorted CD8 T cell subsets from recent-onset T1D subjects treated with alefacept

2020-12-23 | GSE163731 | GEO

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

Project description:The objective of this study was to identify specific gene expression profiles able to predict the response of rheumatoid arthritis patients treated with methotrexate /abatacept (Aba). Thirty six RA patients were received Abatacept. The drug efficacy was evaluated with the DAS28 score after 6 months of treatment according to the EULAR response criteria. Among 36 Aba RA patients, 17 were responders and 19 were classified as no-responders. A blood sample was carried out in patients just before the first injection of treatment in PaxGene tubes. Two color experiments : patient(Cy5)/Control pool (Cy3).

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

EOMES interacts with RUNX3 and BRG1 to promote innate memory cell formation through epigenetic reprogramming

Project description:Memory CD8+ T cells have the ability to provide lifelong immunity against pathogens. Although memory features generally arise after challenge with a foreign antigen, naïve CD8 single positive (SP) thymocytes may acquire phenotypic and functional characteristics of memory cells in response to cytokines such as interleukin-4. This process is associated with the induction of the T-box transcription factor Eomesodermin (EOMES). However, the underlying molecular mechanisms remain ill-defined. Using epigenomic profiling, we show that these innate memory CD8SP cells acquire only a portion of the active enhancer repertoire of conventional memory cells. This reprograming is secondary to EOMES recruitment, mostly to RUNX3-bound enhancers. Furthermore, EOMES is found within chromatin-associated complexes containing BRG1 and promotes the recruitment of this chromatin remodelling factor. Also, the in vivo acquisition of EOMES-dependent program is BRG1-dependent. In conclusion, our results support a strong epigenetic basis for the EOMES-driven establishment of CD8+ T cell innate memory program.

2019-06-06 | PXD014142 | Pride

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