In Situ β Cell Death Promotes Priming of Diabetogenic CD8 T Lymphocytes

Abstract

CTLs are important mediators of pancreatic β cell destruction in the nonobese diabetic mouse model of type 1 diabetes. Cross-presentation of Ag is one means of priming CTLs. The death of Ag-bearing cells has been implicated in facilitating this mode of priming. The role of β cell death in facilitating the onset of spontaneous autoimmune diabetes is unknown. Here, we used an adoptive transfer system to determine the time course of islet-derived Ag presentation to naive β cell-specific CD8 T cells in nonobese diabetic mice and to test the hypothesis that β cell death enhances the presentation of β cell autoantigen. We have determined that β cell death enhances autoantigen presentation. Priming of diabetogenic CD8 T cells in the pancreatic lymph nodes was negligible before 4 wk, progressively increased until 8 wk of age, and was not influenced by gender. Administration of multiple low doses of the β cell toxin streptozotocin augmented in situ β cell apoptosis and accelerated the onset and magnitude of autoantigen presentation to naive CD8 T cells. Increasing doses of streptozotocin resulted in both increased pancreatic β cell death and significantly enhanced T cell priming. These results indicate that in situ β cell death facilitates autoantigen-specific CD8 T cell priming and can contribute to both the initiation and the ongoing amplification of an autoimmune response.

Gut barrier disruption by an enteric bacterial pathogen accelerates insulitis in NOD mice

“…Adoptive transfer, LN preparation and flow cytometry analysis Naive 8.3 NOD CD8 + T cells (islet-specific glucose-6-phosphatase catalytic subunit-related protein [IGRP]-specific [islet antigen] CD8 + T cells) were prepared and purified from the peripheral LNs and spleens of transgenic mice and labelled with CFSE (carboxyfluorescein succinimidyl ester 5 μmol/l; Molecular Probes-Invitrogen, Burlington, ON, Canada) [26]. The labelled cells ( 1×10 7 ) were transferred to WT C. rodentium-infected NOD recipients i.v.…”

“…via a tail vein at 10 days after infection. LN single-cell suspensions were prepared, stained and examined on a FACSCalibur flow cytometer (BD Bioscience, San Jose, CA, USA) as described [26].…”

“…8.3 NOD CD8 + T cells recognise an immuno-dominant peptide from IGRP, termed IGRP 206-214 , a protein expressed by pancreatic beta cells, and these cells are representative of a significant fraction of CD8 + T cells in pancreatic islets at the onset of inflammation [23,28,29]. Adoptive transfer of IGRP-specific (islet antigen) CD8 + T cells [26] into infected NOD mice confirmed an increase in the proliferation and activation of these cells in the pancreatic LNs (Fig. 4a).…”

Trans-presentation of interleukin-15 by interleukin-15 receptor alpha is dispensable for the pathogenesis of autoimmune type 1 diabetes

“…32,33 Similarly, initiation of the immune response following LCMV or Listeria monocytogenes infections is mediated by the cross-presentation of pathogenderived antigens to CD8 1 T cells. 22 IL-15 has been implicated in antigen presenting functions of DCs.…”

Novel Role for RbAp48 in Tissue-Specific, Estrogen Deficiency-Dependent Apoptosis in the Exocrine Glands

“…Activation of caspases may be achieved by several molecular pathways; the best known stimuli triggering the caspase cascade are stimulation of Fas or TNF receptors, release of cytochrome c from the cellular mitochondria, and exposure to granzymes, which are secreted by cytotoxic T cells (3,12,31,37,54). Detailed research on the mechanisms controlling caspase activity will provide better insight into the pathogenesis of autoimmune diseases with special reference to estrogen deficiency.…”