Notch ligation by Delta1 inhibits peripheral immune responses to transplantation antigens by a CD8+ cell–dependent mechanism
Kenneth K. Wong, Matthew J. Carpenter, Lesley L. Young, Susan J. Walker, Grahame McKenzie, Alyson J. Rust, George Ward, Laura Packwood, Karen Wahl, Luc Delriviere, Gerard Hoyne, Paul Gibbs, Brian R. Champion, Jonathan R. Lamb, Margaret J. Dallman
Kenneth K. Wong, Matthew J. Carpenter, Lesley L. Young, Susan J. Walker, Grahame McKenzie, Alyson J. Rust, George Ward, Laura Packwood, Karen Wahl, Luc Delriviere, Gerard Hoyne, Paul Gibbs, Brian R. Champion, Jonathan R. Lamb, Margaret J. Dallman
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Article Immunology

Notch ligation by Delta1 inhibits peripheral immune responses to transplantation antigens by a CD8+ cell–dependent mechanism

Abstract

Notch signaling plays a fundamental role in determining the outcome of differentiation processes in many tissues. Notch signaling has been implicated in T versus B cell lineage commitment, thymic differentiation, and bone marrow hematopoietic precursor renewal and differentiation. Notch receptors and their ligands are also expressed on the surface of mature lymphocytes and APCs, but the effects of Notch signaling in the peripheral immune system remain poorly defined. The aim of the studies reported here was to investigate the effects of signaling through the Notch receptor using a ligand of the Delta-like family. We show that Notch ligation in the mature immune system markedly decreases responses to transplantation antigens. Constitutive expression of Delta-like 1 on alloantigen-bearing cells renders them nonimmunogenic and able to induce specific unresponsiveness to a challenge with the same alloantigen, even in the form of a cardiac allograft. These effects could be reversed by depletion of CD8+ cells at the time of transplantation. Ligation of Notch on splenic CD8+ cells results in a dramatic decrease in IFN-γ with a concomitant enhancement of IL-10 production, suggesting that Notch signaling can alter the differentiation potential of CD8+ cells. These data implicate Notch signaling in regulation of peripheral immunity and suggest a novel approach for manipulating deleterious immune responses.

Authors

Kenneth K. Wong, Matthew J. Carpenter, Lesley L. Young, Susan J. Walker, Grahame McKenzie, Alyson J. Rust, George Ward, Laura Packwood, Karen Wahl, Luc Delriviere, Gerard Hoyne, Paul Gibbs, Brian R. Champion, Jonathan R. Lamb, Margaret J. Dallman

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Characterization of L cell transfectants. (a) MHC class I and II (Kb and...
Characterization of L cell transfectants. (a) MHC class I and II (Kb and Ab, respectively) and MHC Dl1-transfected (Kb/Dl1 and Ab/Dl1) cells were analyzed using flow cytometry. EGFP expression is shown on FL1-H and indicates the level of expression of the transfected Dl1:EGFP bicistronic construct. EGFP expression reflects Dl1 expression. FL1-H, level of green fluorescence. (b) Quantitative RT-PCR for Dl1 transcripts in parental Kb and Ab cells and their Dl1-transfected counterparts. All samples were normalized by assessment of 18s RNA. Mouse embryonic RNA (day 11) was used as a positive control in the experiment, and transcript levels in other samples are expressed relative to this. (c) Flow-cytometric analysis of MHC class I (H-2Kb, left panels) and MHC class II (H-2Ab, right panels) expression on all cell lines using biotinylated AF6-88 (MHC class I) and 1D9 (MHC class II) mAb’s (filled traces) or no first-stage Ab (open traces). All data are representative of at least three repeat experiments. FL2-H, level of red fluorescence.