Presentation of Antigen by Endothelial Cells and Chemoattraction Are Required for Homing of Insulin-specific CD8+ T Cells

Abstract

Activated insulin-specific CD8+ T cells (IS-CD8+ cells) home to the pancreas, destroy β cells, and cause rapid diabetes upon transfer into diabetes-prone NOD mice. Surprisingly, they also cause diabetes in mouse strains that are free of preexistent inflammation. Thus, we hypothesized that islet-specific homing may be in part dependent on IS-CD8+ cells' recognition of the cognate major histocompatibility complex (MHC)/peptide complexes presented by pancreatic endothelial cells, which acquire the antigen (insulin) from β cells. In fact, islet-specific homing was abrogated in mice that lack MHC class I expression, or presentation of the specific peptide, or have impaired insulin secretion. Moreover, we found that IS-CD8+ cells directly recognized pancreatic endothelial cells in islet organ cultures. Triggering of IS-CD8+ cells' T cell receptor (TCR) led to activation of integrins expressed by these cells. In addition, chemokines, particularly SLC (CCL21), were also required for IS-CD8+ cells' adhesion to endothelial monolayers and for successful homing in vivo. Thus, signaling through TCR and chemokine receptors work in concert to assure firm adhesion of T cells to the pancreatic endothelium. The antigen cross-presentation ability of endothelia may therefore contribute to the specificity of homing of activated T lymphocytes to the tissues where antigens are generated by other cell types.

Reduced Thymic Aire Expression and Abnormal NF-κB2 Signaling in a Model of Systemic Autoimmunity

“…However, expression of MHC class II on atypical cell types, including mouse endothelium, has been reported in response to inflammation and linked to IFN-␥, TNF-␣, and LT exposure (37)(38)(39)(40). Endothelial cells do have the capacity to present Ag in an autoimmune setting, dependent on increased levels of the LT-dependent chemokine CCL21, as seen in NZB mice, to enable lymphocyte adhesion (69).…”

Immediate antigen‐specific effector functions byTCR‐transgenic CD8+ NKT cells

“…RIP-mOVA mice express ovalbumin under the rat insulin promoter in the b-cells in the pancreas, and it has been reported that adoptive transfer of 5 Â 10 6 naive OT-I CD8 + T cells (equivalent to about 8.5 Â 10 4 tgNKT) into these animals causes diabetes in all mice [55]. Development of diabetes involves antigen-specific recruitment of CD8 + T cells through antigen-presenting micro-vascular pancreatic endothelial cells [56]. Interestingly, partial depletion of the NK1.1 + cells from adoptively transferred cells reduced the incidence of diabetes induced by the naive OT-I CD8 + T cells from 100% to about 50% of the animals treated (data not shown).…”

Targeting tumors with LIGHT to generate metastasis-clearing immunity

“…In addition, the stroma matrix may directly interfere with T cell priming by reducing the degree of available antigens. The extracellular matrix proteins can directly bind to tumor antigens [18], while the stromal endothelium and fibroblasts may compete with DCs for antigen uptake [19]. Thus, cancer cells embedded in non-malignant stroma may be ignored [11] when tumor antigens are not expressed at a high level, like in most human cancers.…”