Jagged2 Stimulates the Generation of Cytotoxic T Lymphocytes: Relevance to Acute Graft-Versus-Host Disease

Background: Notch receptors and their ligands are evolutionarily conserved transmembrane proteins. Results of gene targeting and cell culture studies have shown that Notch receptors and DSL ligands play important roles in the development of mouse T lymphocytes from common lymphoid progenitors. However, little is known about the functional roles of Notch receptors and DSL ligands in mature T lymphocytes. The observation that naïve mature CD8+ T lymphocytes express NOTCH-2 and effector cytotoxic T lymphocytes express NOTCH-1 and NOTCH-2 suggests that there may be a role(s) for Notch ligands in the generation and/or functionality of cytotoxic T lymphocytes. Methods: In this report, we use a novel fibroblast based Cytolytic Focus Assay to investigate whether a Notch ligand, Jagged2, has any effect on the generation of mouse cytotoxic T lymphocytes. Results: Our results indicate that target cells-expressed Jagged2 functions as a co-stimulator to promote the generation of cytotoxic T lymphocytes from CD8+ T lymphocytes in conjunction with exogenous interleukin-2. The resulting cytotoxic T lymphocytes have the appearance of large granular lymphocytes, are CD8+ TCRβ+ NK1.1-, and readily lyse allogeneic (or xenogeneic) fibroblasts. Conclusions: Target cells-expressed Jagged2 has a co-stimulatory function in the generation of cytotoxic lymphocytes. This activity may be clinically relevant given the well-known fact that the most common sites of acute graft-versus-host disease (i.e. gut, skin and bile duct) are also sites of concentrated DSL ligand expression. We hypothesize that target tissue-expressed DSL ligands may contribute to the pathogenesis of acute graft-versus-host disease in gut, skin and bile duct in recipients of allogeneic hematopoietic cell transplant.