The beta cell-immune cell interface in type 1 diabetes (T1D)

Abstract

Background: T1D is an autoimmune disease in which pancreatic islets of Langerhans are infiltrated by immune cells resulting in the specific destruction of insulin-producing islet beta cells. Our understanding of the factors leading to islet infiltration and the interplay of the immune cells with target beta cells is incomplete, especially in human disease. While murine models of T1D have provided crucial information for both beta cell and autoimmune cell function, the translation of successful therapies in the murine model to human disease has been a challenge.

Scope of review: Here, we discuss current state of the art and consider knowledge gaps concerning the interface of the islet beta cell with immune infiltrates, with a focus on T cells. We discuss pancreatic and immune cell phenotypes and their impact on cell function in health and disease, which we deem important to investigate further to attain a more comprehensive understanding of human T1D disease etiology.

Major conclusions: The last years have seen accelerated development of approaches that allow comprehensive study of human T1D. Critically, recent studies have contributed to our revised understanding that the pancreatic beta cell assumes an active role, rather than a passive position, during autoimmune disease progression. The T cell-beta cell interface is a critical axis that dictates beta cell fate and shapes autoimmune responses. This includes the state of the beta cell after processing internal and external cues (e.g., stress, inflammation, genetic risk) that that contributes to the breaking of tolerance by hyperexpression of human leukocyte antigen (HLA) class I with presentation of native and neoepitopes and secretion of chemotactic factors to attract immune cells. We anticipate that emerging insights about the molecular and cellular aspects of disease initiation and progression processes will catalyze the development of novel and innovative intervention points to provide additional therapies to individuals affected by T1D.

Keywords: Beta cells; Islets; Neoepitopes; T cell infiltrates; Tolerance; Type 1 diabetes.

Figure 1

Schematicshowing howbeta cell phenotype, susceptibility or resistance to autoimmune attack, and external impact could influence the propensity to attract an autoimmune attack. This schematic depicts a hypothetical view of beta cell susceptibility to an autoimmune attack. Beta cells from a healthy, non-risk gene expressing individual are mostly of a healthy phenotype, with only few, if any, beta cells that have a disease susceptible phenotype. Presence of genetic risk increases the probability for autoimmunity. Individual or combined internal and/or external stresses on beta cells subtypes induce (temporary?) resistance to attack with PD-L1 expression or the propensity for disease development with chemoattractant factor secretion and factors such as hyperexpression of HLA class I and epitope/neoepitope presentation.Generated with BioRender.

Figure 2

The beta cell-immune cell interface in T1D. This schematic depicts some of the known components of the beta cell-immune cell interface, though not every aspect of each and how each aspect contributes to pathology in T1D is fully known. Point A: Susceptible beta cells experience additional stress, including increased insulin demand, multiple sources of ER stress, proinflammatory cytokine exposure, or potential viral infection, the effects of which may be further augmented by expression of susceptible HLA and other genetic susceptibilities. Point B: These processes can result in alterations in gene expression, RNA splicing, dysregulation of protein processing and expression, and generation of modified neo-epitopes. Point C: Class I hyperexpression is a hallmark of beta cells in T1D while beta cell expression of Class II is controversial. Islets secreting CXCL10 attract activated, CXCR3 expressing T cells. However, PD-L1 surface expression can counteract activating immune mechanisms. Point D: Both beta cell class I hyperexpression and class II expression could lead to direct increased native and neoepitope presentation to both CD4⁺ and CD8⁺ T cells. Point E: The full breadth of the autoreactive T cell repertoire is unknown and under investigation as is how central tolerance may be broken in T1D. Point F: The full function of other immune cell populations (macrophages, CD4 Tregs, NK cells, B cells, other immune cells?) in islet infiltration and pathology are similarly under investigation.Generated with BioRender.