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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE163732 | GEO | 2020/12/23

REPOSITORIES: GEO

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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.

Project description:Clinical trials of biologic therapies in type 1 diabetes (T1D) aim to mitigate autoimmune destruction of pancreatic β cells through immune perturbation and serve as resources to elucidate immunological mechanisms in health and disease. In the T1DAL trial of alefacept (LFA3-Ig) in recent-onset T1D, endogenous insulin production was preserved in 30% of subjects for 2 years after therapy. Given our previous findings linking exhausted-like CD8+ T cells to beneficial response in T1D trials, we applied unbiased analyses to sorted CD8+ T cells to evaluate their potential role in T1DAL. Using RNA sequencing, we found that greater insulin C-peptide preservation was associated with a module of activation- and exhaustion-associated genes. This signature was dissected into 2 CD8 memory phenotypes through correlation with cytometry data. These cells were hypoproliferative, shared expanded rearranged TCR junctions, and expressed exhaustion-associated markers including TIGIT and KLRG1. The 2 phenotypes could be distinguished by reciprocal expression of CD8+ T and NK cell markers (GZMB, CD57, and inhibitory killer cell immunoglobulin-like receptor [iKIR] genes), versus T cell activation and differentiation markers (PD-1 and CD28). These findings support previous evidence linking exhausted-like CD8+ T cells to successful immune interventions for T1D, while suggesting that multiple inhibitory mechanisms can promote this beneficial cell state.

| S-EPMC7934874 | biostudies-literature

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

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

| PRJNA664761 | ENA

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

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

| PRJNA687377 | ENA

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

Expression data from recent-onset T1D patients and controls

Project description:Naturally occurring FoxP3+CD4+CD25+high regulatory T cells (Tregs) play an important role in dominant tolerance, suppressing auto-reactive CD4+CD25- T cell activity. Although Tregs from T1D subjects are functionally deficient, there is little knowledge of the molecular mechanisms that orchestrate this loss of Treg function. We observed increased apoptosis (by a novel YOPRO-1/7AAD dual staining protocol) and decreased suppression in polyclonal Tregs in the periphery from high at-risk and T1D subjects. We hypothesize that prior to and during the onset of disease, Tregs lack pro-survival signals and are caught up in a relatively deficient cytokine milieu whose effects may be detectable in the periphery. Microarray analysis was performed on un-stimulated Tregs from 12 subjects with newly diagnosed T1D and 15 healthy controls. Keywords: disease-state analysis

2008-02-22 | GSE10586 | GEO

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

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

| PRJNA687381 | ENA

Cognitive subtypes in recent onset psychosis: distinct neurobiological fingerprints?

Project description:In schizophrenia, neurocognitive subtypes can be distinguished based on cognitive performance and they are associated with neuroanatomical alterations. We investigated the existence of cognitive subtypes in shortly medicated recent onset psychosis patients, their underlying gray matter volume patterns and clinical characteristics. We used a K-means algorithm to cluster 108 psychosis patients from the multi-site EU PRONIA (Prognostic tools for early psychosis management) study based on cognitive performance and validated the solution independently (N = 53). Cognitive subgroups and healthy controls (HC; n = 195) were classified based on gray matter volume (GMV) using Support Vector Machine classification. A cognitively spared (N = 67) and impaired (N = 41) subgroup were revealed and partially independently validated (Nspared = 40, Nimpaired = 13). Impaired patients showed significantly increased negative symptomatology (pfdr = 0.003), reduced cognitive performance (pfdr < 0.001) and general functioning (pfdr < 0.035) in comparison to spared patients. Neurocognitive deficits of the impaired subgroup persist in both discovery and validation sample across several domains, including verbal memory and processing speed. A GMV pattern (balanced accuracy = 60.1%, p = 0.01) separating impaired patients from HC revealed increases and decreases across several fronto-temporal-parietal brain areas, including basal ganglia and cerebellum. Cognitive and functional disturbances alongside brain morphological changes in the impaired subgroup are consistent with a neurodevelopmental origin of psychosis. Our findings emphasize the relevance of tailored intervention early in the course of psychosis for patients suffering from the likely stronger neurodevelopmental character of the disease.

| S-EPMC8209013 | biostudies-literature

Association between treatment effect on C-peptide preservation and HbA1c in meta-analysis of glutamic acid decarboxylase (GAD)-alum immunotherapy in recent-onset type 1 diabetes.

Project description: Not available

| S-EPMC9540800 | biostudies-literature

Functional Genomics Analysis of Islets from Recent and Longstanding T1D Reveals the Need for Distinct Approaches to Therapy

Project description:Our current understanding of the pathogenesis of T1D arose in large part from studies using the non-obese diabetic (NOD) mouse model of type 1 diabetes (T1D). Of concern, therapeutic interventions shown to significantly dampen or even reverse disease in mouse models have not successfully translated into interventions in human T1D. The present study addresses this disconnect in research translation by directly analyzing human donor islets from individuals with T1D, aiming to provide insight into disease mechanisms and identify potential target pathways for therapeutic intervention. We obtained human islets from a young individual with short-duration T1D, an older individual with long-duration T1D and three non-diabetic donors, and performed unbiased functional genomic analysis by high depth RNA sequencing on these unique cases. This analysis identified several inflammatory pathways upregulated in short-duration disease, which surprisingly included many components of innate immunity. Subsequent manipulation of one of these pathways/factors in NOD mice resulted in a significant reduction in diabetes progression when inhibition occurred early in disease progression. Taken together our data demonstrates that the direct analysis of human islets is essential for identifying relevant and promising novel targets for translation into effective therapeutic interventions for human T1D.

2018-07-30 | GSE102371 | GEO

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