Entry of diabetogenic T cells into islets induces changes that lead to amplification of the cellular response

Abstract

In an accompanying paper, we find specific localization of diabetogenic T cells only to islets of Langerhans bearing the specific antigen. Instrumental in the specific localization was the presence of intraislet dendritic cells bearing the β-cell-peptide-MHC complex. Here, we report that the entry of diabetogenic CD4 T cells very rapidly triggered inflammatory gene expression changes in islets and vessels by up-regulating chemokines and adhesion molecules. Vascular cell adhesion molecule-1 (VCAM-1) expression was notable in blood vessels, as was intercellular adhesion molecule-1 (ICAM-1). ICAM-1 was also found on β-cells. These expression changes induced the entry of nonspecific T cells that otherwise did not localize to the islets. In contrast to the entry of diabetogenic CD4 T cells, the entrance of nonspecific T cells required a chemokine response and VCAM-1 expression by the islets. IFN-γ was important for the early gene expression changes in the islets. By microarray analysis, we detected up-regulation of a group of IFNinducible genes as early as 8 h post-T-cell transfer. These studies establish that entry of diabetogenic T cells induces a state of receptivity of islets to subsequent immunological insults.T-cell migration | autoimmunity | type 1 diabetes T he entry of T cells to tissues containing antigen-presenting cells (APCs) bearing their protein antigen leads to an inflammatory response. Within a few days, specific cells are difficult to distinguish among the many inflammatory cells made up of various leukocytes: macrophages, dendritic cells (DC), natural killer cells, and neutrophils. These events have been extensively examined, mainly in the case of the central nervous system (CNS) autoreactivity, where activated myelin antigen-specific T cells migrate to the CNS, leading to autoimmune encephalomyelitis (1). Flow of specific and nonspecific T cells into the capillaries of the cerebral vasculature and adherence to endothelial cells has been shown, particularly after inflammation (2-4). The retention of the circulating autoreactive T cells that allows the passage across the blood-brain barrier depends on the presence of class II MHC bearing APC within the perivascular or Virchow-Robin space (5, 6). After specific T cells are in play, they dictate the migration of nonspecific T cells into the CNS (4, 6, 7). Moreover, a random nonspecific entry and exit of T cells has been described in the mouse and rat (4,(8)(9)(10).In the case of autoimmune diabetes, activated diabetogenic CD4 T cells localized only to islets bearing their cognate antigen; thus, in mice bearing hen-egg white lysozyme (HEL) under the insulin promoter (IP-HEL), T cells bearing a transgenic T-cell receptor for HEL peptides only localized to islets bearing HEL. The same was true for the localization of diabetogenic T cells in the NOD model of spontaneous diabetes (11). In both cases, the intraislet DCs were instrumental in the presentation of the peptide-MHC complexes and in the localization of the CD4 T cells. We did not obtain evidence t...

Anti-coreceptor therapy drives selective T cell egress by suppressing inflammation-dependent chemotactic cues

“…Antigen stimulation plays a key role in retention of T cells within the islets (15)(16)(17)(18)(19). Furthermore, TCR signaling is required for IL2 and IFNG transcription, which is downregulated by YTS (35, 36)( Figure 2B).…”

“…T cell-derived IFN-γ for instance, upregulates CXCL9 and CXCL10 production by islet-resident cells, including β cells, resulting in further recruitment of pathogenic CXCR3 + T H 1 cells, and innate effectors (20)(21)(22). Such feed-forward circuits are thought to be common among autoimmune diseases (11,15,18).…”

“…Once islet T cell residency is established, T cell receptor (TCR) signaling drives expression of proinflammatory cytokines, which further stimulates local production of chemotactic ligands (15)(16)(17)(18)(19). T cell-derived IFN-γ for instance, upregulates CXCL9 and CXCL10 production by islet-resident cells, including β cells, resulting in further recruitment of pathogenic CXCR3 + T H 1 cells, and innate effectors (20)(21)(22).…”

Population dynamics of islet-infiltrating cells in autoimmune diabetes

“…Polyclonal populations, unlikely to be antigen specific, accompanied cells from specific clones injected into NOD mice (16). Calderon et al (17) showed that, in transgenic models, the initial entry of antigen-specific cells modifies local conditions, allowing the recruitment of nonspecific T cells. It should also be noted that Significance In many autoimmune diseases, self-reactive lymphocytes lead to immunocyte infiltration in the target tissue, whose evolution over time is regulated.…”

“…chemokine expression resulting from inflammation has the potential to attract T cells to the islets (17,18).…”