Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 37, Pages E7776-E7785Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1707381114
Keywords
diabetes; autoimmunity; immunoregulation
Categories
Funding
- NIH [P01 AI054904, R01EB010011]
- JPB foundation
- Juvenile Diabetes Research Foundation [3-2014-216]
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Type 1 diabetes in the nonobese diabetic mouse stems from an infiltration of the pancreatic islets by a mixed population of immunocytes, which results in the impairment and eventual destruction of insulin-producing beta-cells. Little is known about the dynamics of lymphocyte movement in the pancreas during disease progression. Using advanced intravital imaging approaches and newly created reporter mice (Flt3-BFP2, Mertk-GFP-DTR, Cd4-tdTomato, Cd8a-tdTomato), we show that the autoimmune process initiates first with a T cell infiltration into the islets, where they have restricted mobility but reside and are activated in apposition to CX3CR1(+) macrophages. The main expansion then occurs in the connective tissue outside the islet, which remains more or less intact. CD4(+) and CD8(+) T cells, Tregs, and dendritic cells (DCs) are highly mobile, going along microvascular tracks, while static macrophages (MF) form a more rigid structure, often encasing the islet cell mass. Transient cell-cell interactions are formed between T cells and both MFs and DCs, but also surprisingly between MFs and DCs themselves, possibly denoting antigen transfer. In later stages, extensive islet destruction coincides with preferential antigen presentation to, and activation of, CD8(+) T cells. Throughout the process, Tregs patrol the active compartments, consistent with the notion that they control the activation of many cell types.
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