Intestinal mucosal immunity and type 1 diabetes: Non-negligible communication between gut and pancreas

Abstract

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by T cell-mediated pancreatic β cell loss, resulting in lifelong absolute insulin deficiency and hyperglycaemia. Environmental factors are recognized as a key contributor to the development of T1D, with the gut serving as a primary interface for environmental stimuli. Recent studies have revealed that the alterations in the intestinal microenvironment profoundly affect host immune responses, contributing to the aetiology and pathogenesis of T1D. However, the dominant intestinal immune cells and the underlying mechanisms remain incompletely elucidated. In this review, we provide an overview of the possible mechanisms of the intestinal mucosal system that underpin the pathogenesis of T1D, shedding light on the roles of both non-classical and classical immune cells in T1D. Our goal is to gain insights into how modulating these immune components may hold potential implications for T1D prevention and provide novel perspectives for immune-mediated therapy.

Keywords: gut‐pancreas axis; intestinal mucosal immunity; microbiota; type 1 diabetes; unconventional T cell.

FIGURE 1

Implication of the communication between gut and pancreas in the aetiology of type 1 diabetes. Created in BioRender.com.

FIGURE 2

The gut microbiota, gut barrier, and their surrounding environment together form the intestinal microenvironment. Created in BioRender.com.

FIGURE 3

γδ T cell. We compared the differences in the mechanisms of γδ T cell engagement in human T1D and NOD mice. In human T1D, intestinal inflammation leads to the activation of mucosal immunity, which in turn triggers IL‐17 to destroy islet β cells. Based on the Vγ gene, γδT cells in the intestinal mucosa of NOD mice are classified into Vγ4+, Vγ7+ γδT cells that protect against T1D, and Vγ1+ γδT cells that promote the development of T1D. γδT cells in the spleen secrete TGF‐β for the protection of T1D. Created in BioRender.com.

FIGURE 4

iNKT. iNKT cells differentiate into distinct cell subsets upon recognition of lipid antigens. α‐GalCer offers protection against T1D by stimulating IL‐4 secretion and reducing IFN‐γ secretion by iNKT cells. iNKT17 cells secrete IL‐17 and migrate to the pancreas to facilitate the development of T1D. Created in BioRender.com.

FIGURE 5

MAIT cell. In the homeostasis of NOD mice, MAIT cells migrate to the mucosal barrier and lymphoid organs to secrete IL‐17 and IL‐22 for maintaining the intestinal epithelial barrier. As T1D progresses, MAIT cells with cytotoxic activity migrate to the pancreas and secrete GzB and IFN‐γ to destroy islet β cells. Created in BioRender.com.

FIGURE 6

ILCs. ILCs are divided into three groups based on their phenotype and functional characteristics. ILC3s secrete IL‐17 and GM‐CSF to prevent immune cells from being activated by pathogenic microorganisms, secrete IL‐22 and antimicrobial peptides to maintain the integrity of the intestinal barrier, and secrete IL‐2 to promote the migration of intestinal Tregs to the PLN, thereby protecting against T1D. ILC3s recognize SCFA, inducing Treg cells to protect against T1D. Created in BioRender.com.

FIGURE 7

Classical immune cell. Neutrophils and macrophages infiltrate the intestinal tract of NOD mice. NETs release citrulline histones and directly damage tissues, while macrophages secrete IL‐12 and induce gut‐derived Tc1 cells to migrate to the pancreas to promote the development of T1D. DCs present antigens to induce T cell differentiation, and the balance between Th17/Treg and Th1/Th2 is of great significance for protecting against T1D. In addition, T cells promote B cell activation and secretion of specific sIgA, shaping the gut microbiome and maintaining homeostasis. Created in BioRender.com.