Means, Motive, and Opportunity: Do Non-Islet-Reactive Infiltrating T Cells Contribute to Autoimmunity in Type 1 Diabetes?

In human type 1 diabetes and animal models of the disease, a diverse assortment of immune cells infiltrates the pancreatic islets. CD8+ T cells are well represented within infiltrates and HLA multimer staining of pancreas sections provides clear evidence that islet epitope reactive T cells are present within autoimmune lesions. These bona fide effectors have been a key research focus because these cells represent an intellectually attractive culprit for β cell destruction. However, T cell receptors are highly diverse in human insulitis. This suggests correspondingly broad antigen specificity, which includes a majority of T cells for which there is no evidence of islet-specific reactivity. The presence of “non-cognate” T cells in insulitis raises suspicion that their role could be beyond that of an innocent bystander. In this perspective, we consider the potential pathogenic contribution of non-islet-reactive T cells. Our intellectual framework will be that of a criminal investigation. Having arraigned islet-specific CD8+ T cells for the murder of pancreatic β cells, we then turn our attention to the non-target immune cells present in human insulitis and consider the possible regulatory, benign, or effector roles that they may play in disease. Considering available evidence, we overview the case that can be made that non-islet-reactive infiltrating T cells should be suspected as co-conspirators or accessories to the crime and suggest some possible routes forward for reaching a better understanding of their role in disease.

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What the HLA-I!—Classical and Non-classical HLA Class I and Their Potential Roles in Type 1 Diabetes

Current Diabetes Reports ◽

10.1007/s11892-019-1245-z ◽

2019 ◽

Vol 19 (12) ◽

Cited By ~ 1

Author(s):

Rebecca C. Wyatt ◽

Giacomo Lanzoni ◽

Mark A. Russell ◽

Ivan Gerling ◽

Sarah J. Richardson

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Immune Cells ◽

Age At Onset ◽

Hla Class I ◽

Class I ◽

Β Cells ◽

Disease Etiology ◽

Recent Onset

Abstract Purpose of Review Hyperexpression of classical HLA class I (HLA-I) molecules in insulin-containing islets has become a widely accepted hallmark of type 1 diabetes pathology. In comparison, relatively little is known about the expression, function and role of non-classical subtypes of HLA-I. This review focuses on the current understanding of the non-classical HLA-I subtypes: HLA-E, HLA-F and HLA-G, within and outside the field of type 1 diabetes, and considers the possible impacts of these molecules on disease etiology. Recent Findings Evidence is growing to suggest that non-classical HLA-I proteins are upregulated, both at the RNA and protein levels in the pancreas of individuals with recent-onset type 1 diabetes. Moreover, associations between non-classical HLA-I genotypes and age at onset of type 1 diabetes have been reported in some studies. As with classical HLA-I, it is likely that hyperexpression of non-classical HLA-I is driven by the release of diffusible interferons by stressed β cells (potentially driven by viral infection) and exacerbated by release of cytokines from infiltrating immune cells. Summary Non-classical HLA-I proteins predominantly (but not exclusively) transduce negative signals to immune cells infiltrating at the site of injury/inflammation. We propose a model in which the islet endocrine cells, through expression of non-classical HLA-I are fighting back against the infiltrating immune cells. By inhibiting the activity and function on NK, B and select T cells, the non-classical HLA-I, proteins will reduce the non-specific bystander effects of inflammation, while at the same time still allowing the targeted destruction of β cells by specific islet-reactive CD8+ T cells.

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Tet2 Controls the Responses of β cells to Inflammation in Autoimmune Diabetes

Nature Communications ◽

10.1038/s41467-021-25367-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jinxiu Rui ◽

Songyan Deng ◽

Ana Luisa Perdigoto ◽

Gerald Ponath ◽

Romy Kursawe ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Type 1 Diabetes ◽

Immune Cells ◽

Autoimmune Diabetes ◽

Bone Marrow Transplants ◽

Β Cells ◽

Inflammatory Genes

Abstractβ cells may participate and contribute to their own demise during Type 1 diabetes (T1D). Here we report a role of their expression of Tet2 in regulating immune killing. Tet2 is induced in murine and human β cells with inflammation but its expression is reduced in surviving β cells. Tet2-KO mice that receive WT bone marrow transplants develop insulitis but not diabetes and islet infiltrates do not eliminate β cells even though immune cells from the mice can transfer diabetes to NOD/scid recipients. Tet2-KO recipients are protected from transfer of disease by diabetogenic immune cells.Tet2-KO β cells show reduced expression of IFNγ-induced inflammatory genes that are needed to activate diabetogenic T cells. Here we show that Tet2 regulates pathologic interactions between β cells and immune cells and controls damaging inflammatory pathways. Our data suggests that eliminating TET2 in β cells may reduce activating pathologic immune cells and killing of β cells.

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

Current Diabetes Reports ◽

10.1007/s11892-017-0915-y ◽

2017 ◽

Vol 17 (10) ◽

Cited By ~ 11

Author(s):

Sally C. Kent ◽

Stuart I. Mannering ◽

Aaron W. Michels ◽

Jenny Aurielle B. Babon

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Human Type ◽

Human Type 1 Diabetes

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Faculty Opinions recommendation of Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726906598.793584552 ◽

2021 ◽

Author(s):

Matthias von Herrath ◽

Susanne Pfeiffer

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Antigen Specificity ◽

Self Antigen

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Nonlinear Analysis for a Type-1 Diabetes Model with Focus on T-Cells and Pancreatic β-Cells Behavior

Mathematical and Computational Applications ◽

10.3390/mca25020023 ◽

2020 ◽

Vol 25 (2) ◽

pp. 23

Author(s):

Diana Gamboa ◽

Carlos E. Vázquez ◽

Paul J. Campos

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Cell Population ◽

Closed Loop ◽

Pancreatic Β Cell ◽

Activated Macrophages ◽

Β Cells ◽

Β Cell ◽

Pancreatic Β Cells

Type-1 diabetes mellitus (T1DM) is an autoimmune disease that has an impact on mortality due to the destruction of insulin-producing pancreatic β -cells in the islets of Langerhans. Over the past few years, the interest in analyzing this type of disease, either in a biological or mathematical sense, has relied on the search for a treatment that guarantees full control of glucose levels. Mathematical models inspired by natural phenomena, are proposed under the prey–predator scheme. T1DM fits in this scheme due to the complicated relationship between pancreatic β -cell population growth and leukocyte population growth via the immune response. In this scenario, β -cells represent the prey, and leukocytes the predator. This paper studies the global dynamics of T1DM reported by Magombedze et al. in 2010. This model describes the interaction of resting macrophages, activated macrophages, antigen cells, autolytic T-cells, and β -cells. Therefore, the localization of compact invariant sets is applied to provide a bounded positive invariant domain in which one can ensure that once the dynamics of the T1DM enter into this domain, they will remain bounded with a maximum and minimum value. Furthermore, we analyzed this model in a closed-loop scenario based on nonlinear control theory, and proposed bases for possible control inputs, complementing the model with them. These entries are based on the existing relationship between cell–cell interaction and the role that they play in the unchaining of a diabetic condition. The closed-loop analysis aims to give a deeper understanding of the impact of autolytic T-cells and the nature of the β -cell population interaction with the innate immune system response. This analysis strengthens the proposal, providing a system free of this illness—that is, a condition wherein the pancreatic β -cell population holds and there are no antigen cells labeled by the activated macrophages.

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Determining Antigen Specificity of Human Islet Infiltrating T Cells in Type 1 Diabetes

Frontiers in Immunology ◽

10.3389/fimmu.2019.00365 ◽

2019 ◽

Vol 10 ◽

Author(s):

Maki Nakayama ◽

Aaron W. Michels

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Human Islet ◽

Antigen Specificity

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Su.19. Impaired Function of the Cd4+ T-Cells in Human Type 1 Diabetes Mellitus

Clinical Immunology ◽

10.1016/j.clim.2006.04.446 ◽

2006 ◽

Vol 119 ◽

pp. S166

Author(s):

Tihamer Orban ◽

Janos Kis ◽

Peter Engelmann ◽

Laszlo Szereday ◽

Geoffrey Richman ◽

...

Keyword(s):

Diabetes Mellitus ◽

T Cells ◽

Type 1 Diabetes ◽

Type 1 Diabetes Mellitus ◽

Cd4 T Cells ◽

Human Type ◽

Impaired Function ◽

Human Type 1 Diabetes

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Probiotics and Prebiotics for the Amelioration of Type 1 Diabetes: Present and Future Perspectives

Microorganisms ◽

10.3390/microorganisms7030067 ◽

2019 ◽

Vol 7 (3) ◽

pp. 67 ◽

Cited By ~ 21

Author(s):

Sidharth Mishra ◽

Shaohua Wang ◽

Ravinder Nagpal ◽

Brandi Miller ◽

Ria Singh ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

Immune System ◽

Gut Microbiota ◽

Adaptive Immune Response ◽

Early Years ◽

Autoimmune Response ◽

Β Cells ◽

Environmental Interactions

Type 1-diabetes (T1D) is an autoimmune disease characterized by immune-mediated destruction of pancreatic beta (β)-cells. Genetic and environmental interactions play an important role in immune system malfunction by priming an aggressive adaptive immune response against β-cells. The microbes inhabiting the human intestine closely interact with the enteric mucosal immune system. Gut microbiota colonization and immune system maturation occur in parallel during early years of life; hence, perturbations in the gut microbiota can impair the functions of immune cells and vice-versa. Abnormal gut microbiota perturbations (dysbiosis) are often detected in T1D subjects, particularly those diagnosed as multiple-autoantibody-positive as a result of an aggressive and adverse immunoresponse. The pathogenesis of T1D involves activation of self-reactive T-cells, resulting in the destruction of β-cells by CD8+ T-lymphocytes. It is also becoming clear that gut microbes interact closely with T-cells. The amelioration of gut dysbiosis using specific probiotics and prebiotics has been found to be associated with decline in the autoimmune response (with diminished inflammation) and gut integrity (through increased expression of tight-junction proteins in the intestinal epithelium). This review discusses the potential interactions between gut microbiota and immune mechanisms that are involved in the progression of T1D and contemplates the potential effects and prospects of gut microbiota modulators, including probiotic and prebiotic interventions, in the amelioration of T1D pathology, in both human and animal models.

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