IL-10 inhibits endothelium-dependent T cell costimulation by up-regulation of ILT3/4 in human vascular endothelial cells.
Effects of IL-10 on endothelium-dependent T cell activation have not been investigated in detail. We confirm expression of the IL-10 receptor and effective signaling via STAT-3 in human umbilical vein endothelial cells (HUVEC). In CD4 T cell cocultures with HUVEC, pretreatment of endothelial cells with IL-10 resulted in significant dose-dependent inhibition of CD4 T cell proliferation, which also occurred when IL-10 was removed after pretreatment before starting cocultures. Th1/Th2 polarization of proliferated T cells, endothelial nitric oxide (NO), or IL-12 production were unchanged. However, IL-10 stimulation resulted in up-regulation of SOCS-3, a negative regulator of cytokine secretion, and induction of the inhibitory surface molecules immunoglobulin-like transcript 3 and 4 (ILT3/ILT4) in EC, potentially involving glucocorticoid-induced leucine zipper (GILZ). Addition of blocking antibodies against ILT3/ILT4 to EC/T cell cocultures resulted in nearly complete reestablishment of T cell proliferation. In contrast, addition of soluble ILT3 or overexpression of ILT3 in cocultures significantly reduced T cell proliferation. No induction of foxp3+ regulatory T cells was seen. In conclusion, the T cell costimulatory potential of human EC is markedly suppressed by IL-10 due to up-regulation of ILT3/ILT4, obviously not involving generation of Treg. This identifies a novel action of IL-10 in EC and a potential therapeutical target for local immunomodulation.
Gleissner
Christian A
CA
Department of Cardiology, University Hospital, University of Heidelberg, Heidelberg, Germany.
Zastrow
Arne
A
Klingenberg
Roland
R
Kluger
Martin S
MS
Konstandin
Mathias
M
Celik
Sultan
S
Haemmerling
Susanne
S
Shankar
Vijay
V
Giese
Thomas
T
Katus
Hugo A
HA
Dengler
Thomas J
TJ
D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D018920:Coculture Techniques; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D006131:Growth Inhibitors / Q000502:physiology*; D006801:Humans; D016753:Interleukin-10 / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000502:physiology; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000502:physiology; D011971:Receptors, Immunologic / Q000096:biosynthesis* / Q000502:physiology; D053701:Receptors, Interleukin-10 / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology*
D006131:Growth Inhibitors; C491341:LILRB2 protein, human; C107907:LILRB4 protein, human; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D053701:Receptors, Interleukin-10; D016753:Interleukin-10