Reduced TIGIT Expression on T Cells Links Hyperglycemia to Immune Dysregulation in Type 1 Diabetes

TL;DR

High blood sugar in type 1 diabetes reduces TIGIT+ T cells, which may worsen immune control and autoimmune activity.

Contribution

This study identifies a TIGIT-dependent mechanism linking hyperglycemia to immune dysregulation in type 1 diabetes.

Findings

TIGIT+ T regulatory and conventional T cells are reduced in type 1 diabetes patients compared to healthy controls.

Hyperglycemia decreases TIGIT+ T cell percentages and glucose metabolism in vitro.

Lower TIGIT+ Tconv percentages may promote autoimmune activity under high glucose conditions.

Abstract

What are the main findings?
Type 1 diabetes is characterized by a lower percentage of TIGIT+ CD4-positive T cells.Hyperglycemia reduces the frequency of TIGIT+ and CTLA-4+ T regulatory cells.

Type 1 diabetes is characterized by a lower percentage of TIGIT+ CD4-positive T cells.

Hyperglycemia reduces the frequency of TIGIT+ and CTLA-4+ T regulatory cells.

What are the implications of the main findings?
Reduced TIGIT+ Tregs in type 1 diabetes is associated with impaired glucose metabolism.Hyperglycemia may weaken immune tolerance by targeting TIGIT+ Tregs.Loss of TIGIT+ Tconvs under high glucose may promote autoimmune activity.

Reduced TIGIT+ Tregs in type 1 diabetes is associated with impaired glucose metabolism.

Hyperglycemia may weaken immune tolerance by targeting TIGIT+ Tregs.

Loss of TIGIT+ Tconvs under high glucose may promote autoimmune activity.

T cells play an important role in the development and progression of type 1 diabetes (T1D). Checkpoint receptors regulate T cell activity, and their expression may be linked to the cells’ metabolic state. This study aims to investigate the association between T regulatory (Treg) and T conventional (Tconv) cells expressing various checkpoint inhibitors and glucose metabolism in type 1 diabetes patients and healthy controls (HCs). The study included 28 participants, with 16 of them diagnosed with type 1 diabetes, while 12 constituted a healthy control group. Multicolor flow cytometry, spectrophotometric analysis, and bead-based multiplex assays were utilized for the analyses. The study revealed that the most significant difference in T cell subsets in peripheral blood concerned TIGIT. Compared to healthy subjects, the percentages of TIGIT+ Tregs and TIGIT+ Tconvs were lower in T1D patients. Interestingly, hyperglycemia in in vitro cultures reduced percentages of TIGIT+ Tregs and TIGIT+ Tconvs, and to some extent also CTLA-4+ Tregs. A decreased percentage of these subsets was, in turn, associated with reduced glucose uptake and lower activity of the enzymes responsible for various stages of glucose metabolism. The described associations suggest a negative influence of hyperglycemia in T1D on immune regulation via a TIGIT-dependent mechanism. Hyperglycemia seems to reduce the percentage of highly regulatory TIGIT+ Tregs both in vivo and in vitro, and it is associated with reduced glucose consumption by these cells. At the same time, a reduction in the percentage of TIGIT+ Tconvs under such conditions may facilitate higher activity of Tconvs, including aberrant autoimmune reactions.

Figures