scholarly journals B Quiet: Autoantigen-Specific Strategies to Silence Raucous B Lymphocytes and Halt Cross-Talk with T Cells in Type 1 Diabetes

Biomedicines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 42
Author(s):  
Jamie L. Felton ◽  
Holly Conway ◽  
Rachel H. Bonami
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Beta Cell ◽  
B Lymphocytes ◽  
Cell Function ◽  
Immune Cell ◽  
Disease Risk ◽  
Significant Risk

Islet autoantibodies are the primary biomarkers used to predict type 1 diabetes (T1D) disease risk. They signal immune tolerance breach by islet autoantigen-specific B lymphocytes. T-B lymphocyte interactions that lead to expansion of pathogenic T cells underlie T1D development. Promising strategies to broadly prevent this T-B crosstalk include T cell elimination (anti-CD3, teplizumab), B cell elimination (anti-CD20, rituximab), and disruption of T cell costimulation/activation (CTLA-4/Fc fusion, abatacept). However, global disruption or depletion of immune cell subsets is associated with significant risk, particularly in children. Therefore, antigen-specific therapy is an area of active investigation for T1D prevention. We provide an overview of strategies to eliminate antigen-specific B lymphocytes as a means to limit pathogenic T cell expansion to prevent beta cell attack in T1D. Such approaches could be used to prevent T1D in at-risk individuals. Patients with established T1D would also benefit from such targeted therapies if endogenous beta cell function can be recovered or islet transplant becomes clinically feasible for T1D treatment.

scholarly journals Glycolysis Inhibition Induces Functional and Metabolic Exhaustion of CD4+ T Cells in Type 1 Diabetes

2021 ◽  
Vol 12 ◽  
Author(s):  
Christina P. Martins ◽  
Lee A. New ◽  
Erin C. O’Connor ◽  
Dana M. Previte ◽  
Kasey R. Cargill ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
T Cell ◽  
Cell Function ◽  
T Cell Responses ◽  
Metabolic Reprogramming ◽  
Cell Responses ◽  
T Cell Function

In Type 1 Diabetes (T1D), CD4+ T cells initiate autoimmune attack of pancreatic islet β cells. Importantly, bioenergetic programs dictate T cell function, with specific pathways required for progression through the T cell lifecycle. During activation, CD4+ T cells undergo metabolic reprogramming to the less efficient aerobic glycolysis, similarly to highly proliferative cancer cells. In an effort to limit tumor growth in cancer, use of glycolytic inhibitors have been successfully employed in preclinical and clinical studies. This strategy has also been utilized to suppress T cell responses in autoimmune diseases like Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS), and Rheumatoid Arthritis (RA). However, modulating T cell metabolism in the context of T1D has remained an understudied therapeutic opportunity. In this study, we utilized the small molecule PFK15, a competitive inhibitor of the rate limiting glycolysis enzyme 6-phosphofructo-2-kinase/fructose-2,6- biphosphatase 3 (PFKFB3). Our results confirmed PFK15 inhibited glycolysis utilization by diabetogenic CD4+ T cells and reduced T cell responses to β cell antigen in vitro. In an adoptive transfer model of T1D, PFK15 treatment delayed diabetes onset, with 57% of animals remaining euglycemic at the end of the study period. Protection was due to induction of a hyporesponsive T cell phenotype, characterized by increased and sustained expression of the checkpoint molecules PD-1 and LAG-3 and downstream functional and metabolic exhaustion. Glycolysis inhibition terminally exhausted diabetogenic CD4+ T cells, which was irreversible through restimulation or checkpoint blockade in vitro and in vivo. In sum, our results demonstrate a novel therapeutic strategy to control aberrant T cell responses by exploiting the metabolic reprogramming of these cells during T1D. Moreover, the data presented here highlight a key role for nutrient availability in fueling T cell function and has implications in our understanding of T cell biology in chronic infection, cancer, and autoimmunity.

scholarly journals Footprints of Immune Cells in the Pancreas in Type 1 Diabetes; to “B” or Not to “B”: Is That Still the Question?

2021 ◽  
Vol 12 ◽  
Author(s):  
Pia Leete ◽  
Noel G. Morgan
Keyword(s):  
Type 1 Diabetes ◽  
T Lymphocytes ◽  
Beta Cell ◽  
B Lymphocytes ◽  
Immune Cell ◽  
Cell Loss ◽  
Human Type ◽  
Cd8 T Lymphocytes ◽  
Human Type 1 Diabetes

Significant progress has been made in understanding the phenotypes of circulating immune cell sub-populations in human type 1 diabetes but much less is known about the equivalent populations that infiltrate the islets to cause beta-cell loss. In particular, considerable uncertainties remain about the phenotype and role of B-lymphocytes in the pancreas. This gap in understanding reflects both the difficulty in accessing the gland to study islet inflammation during disease progression and the fact that the number and proportion of islet-associated B-lymphocytes varies significantly according to the disease endotype. In very young children (especially those <7 years at onset) pancreatic islets are infiltrated by both CD8+ T- and CD20+ B-lymphocytes in roughly equal proportions but it is widely held that the CD8+ T-lymphocytes are responsible for driving beta-cell toxicity. By contrast, the role played by B-lymphocytes remains enigmatic. This is compounded by the fact that, in older children and teenagers (those ≥13 years at diagnosis) the proportion of B-lymphocytes found in association with inflamed islets is much reduced by comparison with those who are younger at diagnosis (reflecting two endotypes of disease) whereas CD8+ T-lymphocytes form the predominant population in both groups. In the present paper, we review the current state of understanding and develop a proposal to stimulate further discussion of the roles played by islet-associated B-lymphocytes in human type 1 diabetes. We cite evidence indicating that sites of direct contact can be found between CD8+ and CD20+-lymphocytes in and around inflamed islets and propose that such interactions may be important in determining the efficiency of beta cell killing.

scholarly journals The Multiple Roles of B Lymphocytes in the Onset and Treatment of Type 1 Diabetes: Interactions between B Lymphocytes and T Cells

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Yangfan Xiao ◽  
Chao Deng ◽  
Zhiguang Zhou
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
B Cells ◽  
B Lymphocytes ◽  
Cell Function ◽  
Autoimmune Diabetes ◽  
Β Cell Function ◽  
Nonobese Diabetic Mice ◽  
The Impact

Although type 1 diabetes is thought to be an organ-specific autoimmune disease, mediated by effective CD4+ and CD8+ T cells, it has recently become clear that B cells participate in the initiation and progress of this disease. Indeed, B cell deletion can prevent or reverse autoimmune diabetes in nonobese diabetic mice and even result in partially remaining β cell function in patients with new-onset type 1 diabetes. This review summarizes the dual role of B cells in this process not only of pathogenic effect but also of immunoregulatory function in type 1 diabetes. We focus on the impact that B cells have on regulating the activation, proliferation, and cytokine production of self-reactive T cells along with regulatory T cells, with the aim of providing a better understanding of the interactions between T and B cells in immunopathogenesis and improving the efficacy of interventions for clinical practice.

scholarly journals Activation of T cell checkpoint pathways during beta-cell antigen presentation by engineered dendritic cells promotes protection of non-obese diabetic mice from type 1 diabetes

2021 ◽  
Author(s):  
Radhika R Gudi ◽  
Nicolas Perez ◽  
Subha Karumuthil-Melethil ◽  
Gongbo Li ◽  
Chenthamarakshan Vasu
Keyword(s):  
Type 1 Diabetes ◽  
Dendritic Cells ◽  
T Cell ◽  
Beta Cell ◽  
Cell Function ◽  
Cell Antigen ◽  
Effector T Cell ◽  
Selective Ligands ◽  
Checkpoint Receptors

Defective immune regulation has been recognized in type 1 diabetes (T1D). Immune regulatory T cell check-point receptors, which are generally upregulated on activated T cells, have been the molecules of attention as therapeutic targets for enhancing immune response in tumor therapy. We reported that dendritic cells (DCs) that are engineered to express selective ligands for checkpoint receptors can induce effective T cell tolerance in antigen-immunization models. Here, we show that, compared to engineered control-DCs, pancreatic beta-cell antigen (BcAg) presentation by engineered tolerogenic-DCs (tDCs) that express CTLA4 selective ligand (B7.1wa) or a combination of CTLA4, PD1 and BTLA selective ligands (B7.1wa, PD-L1, and HVEM-CRD1 respectively; multiligand-DCs) causes an increase in regulatory cytokine and T cell (Treg) responses and suppression of the effector T cell function. Non-obese diabetic (NOD) mice treated with BcAg-pulsed CTLA4-ligand-DCs and multiligand-DCs at pre-diabetic and early-hyperglycemic stages showed significantly lower degree of insulitis, higher frequencies of insulin-positive islets, profound delay in, and reversal of, hyperglycemia for a significant duration. Immune cells from the tDC treated mice not only produced lower amounts of IFNgamma; and higher amounts of IL10 and TGF-beta1 upon BcAg challenge, but also failed to induce hyperglycemia upon adoptive transfer. While both CTLA4-ligand-DCs and multiligand-DCs were effective in producing a tolerogenic effect, multiligand-DC treatment produced an overall higher modulatory effect on effector T cell function and disease outcome. Overall, these studies show that enhanced engagement of T cell checkpoint receptors during BcAg presentation can effectively prevent and suppress autoimmunity in T1D.

294-OR: Type 1 Diabetes Patients with Residual Beta-Cell Function Display Improved Time in Euglycemia and Less Glycaemic Fluctuation after Exercise

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 294-OR
Author(s):  
GUY S. TAYLOR ◽  
KIERAN SMITH ◽  
JADINE SCRAGG ◽  
AYAT BASHIR ◽  
RICHARD A. ORAM ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Diabetes Patients

scholarly journals Autoantigen Treatment in Type 1 Diabetes: Unsolved Questions on How to Select Autoantigen and Administration Route

2020 ◽  
Vol 21 (5) ◽  
pp. 1598 ◽  
Author(s):  
Johnny Ludvigsson
Keyword(s):  
Type 1 Diabetes ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Human Subjects ◽  
Subcutaneous Administration ◽  
Acid Decarboxylase ◽  
Recent Onset ◽  
Prevention Trials

Autoantigen treatment has been tried for the prevention of type 1 diabetes (T1D) and to preserve residual beta-cell function in patients with a recent onset of the disease. In experimental animal models, efficacy was good, but was insufficient in human subjects. Besides the possible minor efficacy of peroral insulin in high-risk individuals to prevent T1D, autoantigen prevention trials have failed. Other studies on autoantigen prevention and intervention at diagnosis are ongoing. One problem is to select autoantigen/s; others are dose and route. Oral administration may be improved by using different vehicles. Proinsulin peptide therapy in patients with T1D has shown possible minor efficacy. In patients with newly diagnosed T1D, subcutaneous injection of glutamic acid decarboxylase (GAD) bound to alum hydroxide (GAD-alum) can likely preserve beta-cell function, but the therapeutic effect needs to be improved. Intra-lymphatic administration may be a better alternative than subcutaneous administration, and combination therapy might improve efficacy. This review elucidates some actual problems of autoantigen therapy in the prevention and/or early intervention of type 1 diabetes.

Sign in / Sign up

Export Citation Format

Share Document