title: An evolving autoimmune microenvironment regulates the quality of effector T cell restimulation and function.
abstract: 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.
authors.affiliation: Department of Biomedical Research, National Jewish Health, Denver, CO 80206;Department of Immunology, University of Colorado Denver, Aurora, CO 80045; and friedmanr@njhealth.org.
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Friedman
authors.affiliation: Department of Biomedical Research, National Jewish Health, Denver, CO 80206;Department of Immunology, University of Colorado Denver, Aurora, CO 80045; and.
authors.forename: Robin S
authors.initials: RS
authors.lastname: Lindsay
authors.affiliation: Department of Biomedical Research, National Jewish Health, Denver, CO 80206;Department of Immunology, University of Colorado Denver, Aurora, CO 80045; and.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Lilly
authors.affiliation: Departments of Surgery and.
authors.forename: Vinh
authors.initials: V
authors.lastname: Nguyen
authors.affiliation: Pathology, University of California, San Francisco, CA 94143.
authors.forename: Caitlin M
authors.initials: CM
authors.lastname: Sorensen
authors.affiliation: Department of Biomedical Research, National Jewish Health, Denver, CO 80206;Department of Immunology, University of Colorado Denver, Aurora, CO 80045; and.
authors.forename: Jordan
authors.initials: J
authors.lastname: Jacobelli
authors.affiliation: Pathology, University of California, San Francisco, CA 94143.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Krummel
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002450:Cell Communication / Q000276:immunology*; D002478:Cells, Cultured; D060833:Cellular Microenvironment / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D007371:Interferon-gamma / Q000276:immunology; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma
keywords: 2-photon microscopy; T-lymphocyte reactivation; autoimmunity