title: Intravital imaging of CTLs killing islet cells in diabetic mice.
abstract: Type 1 diabetes (T1D) is caused by autoimmune destruction of the insulin-producing β cells in the pancreatic islets, which are essentially mini-organs embedded in exocrine tissue. CTLs are considered to have a predominant role in the autoimmune destruction underlying T1D. Visualization of CTL-mediated killing of β cells would provide new insight into the pathogenesis of T1D, but has been technically challenging to achieve. Here, we report our use of intravital 2-photon imaging in mice to visualize the dynamic behavior of a virally expanded, diabetogenic CTL population in the pancreas at cellular resolution. Following vascular arrest and extravasation, CTLs adopted a random motility pattern throughout the compact exocrine tissue and displayed unimpeded yet nonlinear migration between anatomically nearby islets. Upon antigen encounter within islets, a confined motility pattern was acquired that allowed the CTLs to scan the target cell surface. A minority of infiltrating CTLs subsequently arrested at the β cell junction, while duration of stable CTL-target cell contact was on the order of hours. Slow-rate killing occurred in the sustained local presence of substantial numbers of effector cells. Collectively, these data portray the kinetics of CTL homing to and between antigenic target sites as a stochastic process at the sub-organ level and argue against a dominant influence of chemotactic gradients.
authors: Type 1 Diabetes Center, The La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors: Ken
authors: K
authors: Coppieters
authors: Natalie
authors: N
authors: Amirian
authors: Matthias
authors: M
authors: von Herrath
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000235:genetics; D002465:Cell Movement / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000473:pathology; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology*; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D036641:Microscopy, Fluorescence, Multiphoton; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000473:pathology
chemical_list: D000956:Antigens, Viral; D049452:Green Fluorescent Proteins