An evolving autoimmune microenvironment regulates the quality of effector T cell restimulation and function

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-06, Vol.111 (25), p.9223-9228
• Main Authors: Friedman, Rachel S., Lindsay, Robin S., Lilly, Jason K., Nguyen, Vinh, Sorensen, Caitlin M., Jacobelli, Jordan, Krummel, Matthew F.
• Format: Article
• Language: English
• Subjects: Animals; Antigen-Presenting Cells - immunology; Antigen-Presenting Cells - pathology; Autoimmune diseases; Biological Sciences; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Cell Communication - immunology; Cells, Cultured; Cellular Microenvironment - immunology; Cytokines; Cytotoxicity; Dendritic cells; Diabetes; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - pathology; Disease models; Imaging; Infiltration; Interferon-gamma - immunology; Lymphocytes; Mice; Microscopy; Pancreas; Pathogens; Receptors, Antigen, T-Cell - immunology; Signal Transduction - immunology; T cell antigen receptors; T lymphocytes; Type 1 diabetes mellitus
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1322193111

Defining the processes of autoimmune attack of tissues is important for inhibiting continued tissue destruction. In type 1 diabetes, it is not known how cytotoxic effector T cell responses evolve over time in the pancreatic islets targeted for destruction. We used two-photon microscopy of live, intact, individual islets to investigate how progression of islet infiltration altered the behavior of infiltrating islet-specific CD8 + T cells. During early-islet infiltration, T-cell interactions with CD11c + antigen-presenting cells (APCs) were stable and real-time imaging of T cell receptor (TCR) clustering provided evidence of TCR recognition in these stable contacts. Early T cell—APC encounters supported production of IFN-γ by T effectors, and T cells at this stage also killed islet APCs. At later stages of infiltration, T-cell motility accelerated, and cytokine production was lost despite the presence of higher numbers of infiltrating APCs that were able to trigger T-cell signaling in vitro. Using timed introduction of effector T cells, we demonstrate that elements of the autoimmune-tissue microenvironment control the dynamics of autoantigen recognition by T cells and their resulting pathogenic effector functions.