Demonstration of Tissue Resident Memory CD8 T Cells in Insulitic Lesions in Adult Patients with Recent-Onset Type 1 Diabetes

Kuric, Enida; Seiron, Peter; Krogvold, Lars; Edwin, Bjørn; Buanes, Trond; Hanssen, Kristian F.; Skog, Oskar; Dahl‐Jørgensen, Knut; Korsgren, Olle

doi:10.1016/j.ajpath.2016.11.002

Cited by 63 publications

(56 citation statements)

References 37 publications

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“…12,107 In a study of insulitic lesions in biopsies from recent-onset T1D, a substantial proportion of the CD8+ T cells were found to be tissueresident memory T cells (T RM cells). 118 The T RM cells represented 40% of the total number of CD8 + T cells per inflamed islet, a proportion of T RM cells similar to that previously described in skin lesions of psoriasis. 119 T RM cells constitute a subset of memory T cells that persist for years at the site of a previous infection without persistence of antigen stimulation, and they provide rapid immune protection against re-infection via the same entry port.…”

Section: Islet-autoreactive Cd8 + T Cells In the Peripheral Blood Weresupporting

confidence: 73%

“…In a study of insulitic lesions in biopsies from recent‐onset T1D, a substantial proportion of the CD8+ T cells were found to be tissue‐resident memory T cells (T RM cells) . The T RM cells represented ~40% of the total number of CD8 + T cells per inflamed islet, a proportion of T RM cells similar to that previously described in skin lesions of psoriasis …”

Section: Role Of the Immune System In T1dsupporting

confidence: 68%

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Aetiology of type 1 diabetes: Physiological growth in children affects disease progression

Skog

Korsgren

2017

Diabetes Obesity Metabolism

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The prevailing view is that type 1 diabetes (T1D) develops as a consequence of a severe decline in β-cell mass resulting from T-cell-mediated autoimmunity; however, progression from islet autoantibody seroconversion to overt diabetes and finally to total loss of C-peptide production occurs in most affected individuals only slowly over many years or even decades. This slow disease progression should be viewed in relation to the total β-cell mass of only 0.2 to 1.5 g in adults without diabetes. Focal lesions of acute pancreatitis with accumulation of leukocytes, often located around the ducts, are frequently observed in people with recent-onset T1D, and most patients display extensive periductal fibrosis, the end stage of inflammation. An injurious inflammatory adverse event, occurring within the periductal area, may have negative implications for islet neogenesis, dependent on stem cells residing within or adjacent to the ductal epithelium. This could in part prevent the 30-fold increase in β-cell mass that would normally occur during the first 20 years of life. This increase occurs in order to maintain glucose metabolism during the physiological increases in insulin production that are required to balance the 20-fold increase in body weight during childhood and increased insulin resistance during puberty. Failure to expand β-cell mass during childhood would lead to clinically overt T1D and could help to explain the apparently more aggressive form of T1D occurring in growing children when compared with that observed in affected adults.

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Section: Islet-autoreactive Cd8 + T Cells In the Peripheral Blood Weresupporting

confidence: 73%

Section: Role Of the Immune System In T1dsupporting

confidence: 68%

Aetiology of type 1 diabetes: Physiological growth in children affects disease progression

Skog

Korsgren

2017

Diabetes Obesity Metabolism

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“…The CD8 + T cells were tissue resident memory T cells (T RM ) (CD8 + CD69 + CD103 + ), but without expression of mRNA species associated with acute cytotoxicity or inflammation [55•]. In contrast, interferon-stimulated genes and CXCL10 were shown to be upregulated in the islet core as compared to peri-islet tissue [56•].…”

Section: Pancreatic Histology and Autoreactive T Cells In T1dmentioning

confidence: 99%

Deciphering the Pathogenesis of Human Type 1 Diabetes (T1D) by Interrogating T Cells from the “Scene of the Crime”

et al. 2017

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Purpose of Review Autoimmune-mediated destruction of insulin-producing β-cells within the pancreas results in type 1 diabetes (T1D), which is not yet preventable or curable. Previously, our understanding of the β-cell specific T cell repertoire was based on studies of autoreactive T cell responses in the peripheral blood of patients at risk for, or with, T1D; more recently, investigations have included immunohistochemical analysis of some T cell specificities in the pancreas from organ donors with T1D. Now, we are able to examine live, islet-infiltrating T cells from donors with T1D. Recent Findings Analysis of the T cell repertoire isolated directly from the pancreatic islets of donors with T1D revealed pro-inflammatory T cells with targets of known autoantigens, including proinsulin and glutamic acid decarboxylase, as well as modified autoantigens. Summary We have assayed the islet-infiltrating T cell repertoire for autoreactivity and function directly from the inflamed islets of T1D organ donors. Design of durable treatments for prevention of or therapy for T1D requires understanding this repertoire.

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“…Early investigations implied that CD8+ T cells are likely to play a major role in the process, and this has been confirmed in most subsequent work [21,22,24,35]. These are generally assumed to represent CD8+ 'cytotoxic T cells', but this view has been brought into question by evidence implying that islet-associated CD8+ cells display features that are more reminiscent of tissue resident memory T cells [36,37]. Thus, further characterization of the CD8+ cells present in inflamed islets is clearly required; not least, among people with Type 1 diabetes of different ages (see below).…”

Section: Insulitis: a Heterogeneous Process In Type 1 Diabetes?mentioning

confidence: 98%

Bringing the human pancreas into focus: new paradigms for the understanding of Type 1 diabetes

Morgan

2017

Diabet. Med.

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Type 1 diabetes affects increasingly large numbers of people globally (including at least half a million children under the age of 14 years) and it remains an illness with life-long and often devastating consequences. It is surprising, therefore, that the underlying aetiology of Type 1 diabetes remains poorly understood. This is largely because the cellular and molecular processes leading to the loss of β cells in the pancreas have rarely been studied at, or soon after, the onset of disease. Where such studies have been undertaken, a number of surprises have emerged which serve to challenge conventional wisdom. In particular, it is increasingly understood that the process of islet inflammation (insulitis) is much less florid in humans than in certain animal models. Moreover, the profile of immune cells involved in the inflammatory attack on β cells is variable and this variation occurs at the level of individual patients. As a result, two distinct profiles of insulitis have now been defined that are differentially aggressive and that might, therefore, require specifically tailored therapeutic approaches to slow the progression of disease. In addition, the outcomes are also different in that the more aggressive form (termed 'CD20Hi') is associated with extensive β-cell loss and an early age of disease onset (<7 years), while the less aggressive profile (known as 'CD20Lo') is associated with later onset (>13 years) and the retention of a higher proportion of residual β cells. In the present review, these new findings are explained and their implications evaluated in terms of future therapies.

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Demonstration of Tissue Resident Memory CD8 T Cells in Insulitic Lesions in Adult Patients with Recent-Onset Type 1 Diabetes

Cited by 63 publications

References 37 publications

Aetiology of type 1 diabetes: Physiological growth in children affects disease progression

Aetiology of type 1 diabetes: Physiological growth in children affects disease progression

Deciphering the Pathogenesis of Human Type 1 Diabetes (T1D) by Interrogating T Cells from the “Scene of the Crime”

Bringing the human pancreas into focus: new paradigms for the understanding of Type 1 diabetes

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