Autoreactive CD8+ T cell exhaustion distinguishes subjects with slow type 1 diabetes progression

Wiedeman, Alice; Muir, Virginia S.; Rosasco, Mario G.; DeBerg, Hannah A.; Presnell, Scott; Haas, Bertrand; Dufort, Matthew J.; Speake, Cate; Greenbaum, Carla J.; Serti, Elisavet; Nepom, Gerald T.; Blahnik, Gabriele; Kus, Anna; James, Eddie A.; Linsley, Peter S.; Long, S. Alice

doi:10.1172/jci126595

Cited by 113 publications

(120 citation statements)

References 70 publications

(103 reference statements)

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“…These results suggest that beta cell-specific CD8 + T cells have the capacity to acquire an epigenetic program associated with restricted fate-potential and raise the possibility that therapeutic approaches that promote tolerance can be reinforced by epigenetic mechanisms. Further supporting the link between the mechanisms that preserve T cell stemness and pancreatic islet destruction, a recent publication describes that the rate of T1D disease progression is inversely related to the establishment of an exhaustion phenotype among beta cell-specific CD8 + T cells 34 . To attenuate the harmful nature of the beta cell-specific CD8 + T cells, significant efforts have been mounted to develop new therapeutic strategies to induce tolerance among these autoreactive CD8 + T cells.…”

Section: Discussionmentioning

confidence: 88%

Beta cell-specific CD8+ T cells maintain stem cell memory-associated epigenetic programs during type 1 diabetes

Abdelsamed

Zebley

Nguyen³

et al. 2020

Nat Immunol

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The pool of beta cell-specific CD8 + T-cells in type 1 diabetes (T1D) sustains an autoreactive potential despite having access to a constant source of antigen. To investigate the long-lived nature of these cells, we established a DNA methylation-based T cell “multipotency index” and found that beta cell-specific CD8 + T-cells retained a stem-like epigenetic multipotency score. Single cell ATAC-seq analysis confirmed the co-existence of naive and effector-associated epigenetic programs in individual beta cell-specific CD8 + T-cells. Assessment of beta cell-specific CD8 + T-cell anatomical distribution and the establishment of stem-associated epigenetic programs revealed that self-reactive CD8 + T-cells isolated from murine lymphoid tissue retained developmentally plastic phenotypic and epigenetic profiles relative to the same cells isolated from the pancreas. Collectively, these data provide new insight into the longevity of beta cell-specific CD8 + T cell responses, and document the utility of this novel methylation-based multipotency index for investigating human and mouse CD8 + T-cell differentiation.

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Section: Discussionmentioning

confidence: 88%

Beta cell-specific CD8+ T cells maintain stem cell memory-associated epigenetic programs during type 1 diabetes

Abdelsamed

Zebley

Nguyen³

et al. 2020

Nat Immunol

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“…T-cell exhaustion is an important mechanism to maintain immune homeostasis and prevent autoimmune diseases including T1D (7). In support to this idea, a recent study demonstrated that slow T1D progression was associated with an exhaustion-like profile on islet-reactive T cells, with expression of multiple inhibitory receptors (including PD-1), limited cytokine production, and reduced proliferative capacity (31). Along the same line, an increase in circulating exhausted T cells predicted response to anti-CD3 therapy in T1D (32).…”

Section: The Pd-1/pd-l1 Axis Promotes Beta Cell Tolerance and Preventmentioning

confidence: 96%

Role of the PD-1/PD-L1 Dyad in the Maintenance of Pancreatic Immune Tolerance for Prevention of Type 1 Diabetes

Falcone

Fousteri

2020

Front. Endocrinol.

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The human pancreas, like almost all organs in the human body, is immunologically tolerated despite the presence of innate and adaptive immune cells that promptly mediate protective immune responses against pathogens in situ. The PD-1/PD-L1 inhibitory pathway seems to play a key role in the maintenance of immune tolerance systemically and within the pancreatic tissue. Tissue resident memory T cells (TRM), T regulatory cells (Treg), macrophages and even β cells exhibit PD-1 or PD-L1 expression that contributes in controlling pancreatic immune homeostasis and tolerance. Dysregulation of the PD-1/PD-L1 axis as shown by animal studies and our recent experience with checkpoint inhibitory blockade in humans can lead to immune dysfunctions leading to chronic inflammatory disease and to type 1 diabetes (T1D) in genetically susceptible individuals. In this review, we discuss the role of the PD-1/PD-L1 axis in pancreatic tissue homeostasis and tolerance, speculate how genetic and environmental factors can regulate the PD-1/PD-L1 pathway, and discuss PD-1/PD-L1-based therapeutic approaches for pancreatic islet transplantation and T1D treatment.

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“…During T1D development, CD8 + T cells are the principal T cell type infiltrating the pancreatic islets (4,5). While some reports suggest that the numbers of islet-reactive CD8 + T cells in the blood are higher in patients with T1D than those without the disease (6,7), more recent data question this observation (8)(9)(10). Moreover, preproinsulin (PPI) was recognized by peripheral blood CD8 + T cells (at low frequencies of 1:10 4 to 1:10 6 ) in healthy donors (11).…”

Section: Introductionmentioning

confidence: 99%

The healthy exocrine pancreas contains preproinsulin-specific CD8 T cells that attack islets in type 1 diabetes

et al. 2020

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Preproinsulin (PPI) is presumably a crucial islet autoantigen found in patients with type 1 diabetes (T1D) but is also recognized by CD8+ T cells from healthy individuals. We quantified PPI-specific CD8+ T cells within different areas of the human pancreas from nondiabetic controls, autoantibody-positive donors, and donors with T1D to investigate their role in diabetes development. This spatial cellular quantitation revealed unusually high frequencies of autoreactive CD8+ T cells supporting the hypothesis that PPI is indeed a key autoantigen. To our surprise, PPI-specific CD8+ T cells were already abundantly present in the nondiabetic pancreas, thus questioning the dogma that T1D is caused by defective thymic deletion or systemic immune dysregulation. During T1D development, these cells accumulated in and around islets, indicating that an islet-specific trigger such as up-regulation of major histocompatibility complex class I might be essential to unmask beta cells to the immune system.

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Autoreactive CD8+ T cell exhaustion distinguishes subjects with slow type 1 diabetes progression

Cited by 113 publications

References 70 publications

Beta cell-specific CD8+ T cells maintain stem cell memory-associated epigenetic programs during type 1 diabetes

Beta cell-specific CD8+ T cells maintain stem cell memory-associated epigenetic programs during type 1 diabetes

Role of the PD-1/PD-L1 Dyad in the Maintenance of Pancreatic Immune Tolerance for Prevention of Type 1 Diabetes

The healthy exocrine pancreas contains preproinsulin-specific CD8 T cells that attack islets in type 1 diabetes

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