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Immune cell crosstalk in type 1 diabetes

Key Points

  • This review describes the ways in which cells of the innate immune system have a role in both the pathogenesis and the prevention of the autoimmune disease type 1 diabetes.

  • Epidemiological studies have highlighted a role for both genetic and environmental factors in the development of diabetes.

  • An overview is provided of the ways in which infectious agents have the potential to modulate type 1 diabetes through their effects on the crosstalk between the innate and adaptive arms of the immune response.

Abstract

The development of type 1 diabetes involves a complex interaction between pancreatic β-cells and cells of both the innate and adaptive immune systems. Analyses of the interactions between natural killer (NK) cells, NKT cells, different dendritic cell populations and T cells have highlighted how these different cell populations can influence the onset of autoimmunity. There is evidence that infection can have either a potentiating or inhibitory role in the development of type 1 diabetes. Interactions between pathogens and cells of the innate immune system, and how this can influence whether T cell activation or tolerance occurs, have been under close scrutiny in recent years. This Review focuses on the nature of this crosstalk between the innate and the adaptive immune responses and how pathogens influence the process.

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Figure 1: Molecules expressed by pancreatic β-cells involved in their destruction or protection.
Figure 2: Cellular and molecular mechanisms in the development or prevention of type 1 diabetes.
Figure 3: Effects of viral infection on the regulation of type 1 diabetes.

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Acknowledgements

We apologize to all the authors whose work we could not cite owing to space constrictions. The Cooke laboratory is supported by The Wellcome Trust, Medical Research Council (MRC) and Diabetes UK. P.Z. is supported by the MRC. The Lehuen laboratory is supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), Agence Nationale de la Recherche (ANR-GENOPAT) and the European Foundation for the Study of Diabetes (EFSD).

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Glossary

Non-obese diabetic (NOD) mice

Mice that spontaneously develop type 1 diabetes as a result of islet antigen-specific T cell-mediated destruction of pancreatic β-cells.

X-linked agammaglobulinaemia

A human immunodeficiency that is caused by mutations in the gene encoding Bruton's tyrosine kinase (BTK) (which is located on the X chromosome).These mutations result in a block in B cell maturation and in poor antibody production. A naturally occurring mouse mutant of BTK, X-linked immune deficiency, is associated with less severe disease.

Non-obese resistant (NOR) mice

NOR mice have the identical T cell developmental background as NOD mice, but they do not spontaneously develop type 1 diabetes.

BDC2.5 TCR-transgenic NOD mice

T cells in these mice express a TCR specific for a pancreatic antigen but, interestingly, these mice have a decreased incidence of type 1 diabetes and develop a non-invasive insulitis. These mice are used as donors of islet antigen-specific CD4+ T cells and manipulation of these mice, such as injection of blocking CTLA4-specific antibody and infection with coxsackie virus B4, induces rapid type 1 diabetes.

RIP–LCMV transgenic model

A transgenic mouse model of type 1 diabetes in which peptides derived from lymphocytic choriomeningitis (LCMV) are expressed in the pancreas under the control of the rat insulin promoter (RIP). Infection of the mice with LCMV leads to the development of type 1 diabetes as a result of infiltrating CD8+ effector T cells.

Perforin

A component of cytolytic granules that participates in the permeabilization of plasma membranes, allowing granzymes and other cytotoxic components to enter target cells.

Peripheral tolerance

The lack of self responsiveness of mature lymphocytes in the periphery to specific antigens. These mechanisms control potentially self-reactive lymphocytes that have escaped central tolerance. Peripheral tolerance is associated with the suppression of production of self-reactive antibodies by B cells and inhibition of self-reactive effector cells, such as cytotoxic T lymphocytes.

T cell anergy

A state of T cell unresponsiveness to antigen-specific stimulation. It can be induced by stimulation with a large amount of specific antigen in the absence of the engagement of co-stimulatory molecules.

Indoleamine 2,3-dioxygenase

(IDO). An intracellular haem-containing enzyme that catalyses the oxidative catabolism of tryptophan. IDO suppresses T cell responses and promotes immune tolerance in mammalian pregnancy, tumour resistance, chronic infection, autoimmunity and allergic inflammation.

Invariant NKT (iNKT) cells

Lymphocytes that express a particular variable gene segment, Vα14 (in mice) and Vα24 (in humans), precisely rearranged to a particular Jα (joining) gene segment to yield T cell receptor α-chains that have an invariant sequence. Typically, these cells co-express cell surface markers that are encoded by the NK locus, and they are activated by recognition of CD1d, particularly when α-galactosylceramide is bound in the groove of CD1d.

Molecular mimicry

Resemblance between epitopes contained in microbial and host proteins, leading to cross-reactivity of T cells in the host.

Insulitis

An infiltration of lymphocytes into pancreatic islets during the progression of type 1 diabetes. Insulitis can be innocuous or destructive.

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Lehuen, A., Diana, J., Zaccone, P. et al. Immune cell crosstalk in type 1 diabetes. Nat Rev Immunol 10, 501–513 (2010). https://doi.org/10.1038/nri2787

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