Presentation of antigen by endothelial cells and chemoattraction are required for homing of insulin-specific CD8+ T cells.
Activated insulin-specific CD8(+) T cells (IS-CD8(+) cells) home to the pancreas, destroy beta 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 beta 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.
Savinov
Alexei Y
AY
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Wong
F Susan
FS
Stonebraker
Austin C
AC
Chervonsky
Alexander V
AV
D000818:Animals; D017951:Antigen Presentation; D015703:Antigens, CD; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D002633:Chemotaxis; D046508:Culture Techniques; D003921:Diabetes Mellitus, Experimental / Q000276:immunology; D000071063:Endoglin; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology*; D005260:Female; D005805:Genes, MHC Class I; D051273:Glucose Transporter Type 2; D007328:Insulin / Q000276:immunology*; D007515:Islets of Langerhans / Q000098:blood supply / Q000276:immunology*; D008285:Major Histocompatibility Complex; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D010179:Pancreas / Q000098:blood supply / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000378:metabolism; D037342:Pertussis Toxin / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D051273:Glucose Transporter Type 2; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine; D019010:Vascular Cell Adhesion Molecule-1; D037342:Pertussis Toxin