title: CD26-mediated induction of EGR2 and IL-10 as potential regulatory mechanism for CD26 costimulatory pathway.
abstract: CD26 is associated with T cell signal transduction processes as a costimulatory molecule, and CD26(+) T cells have been suggested to be involved in the pathophysiology of diverse autoimmune diseases. Although the cellular and molecular mechanisms involved in CD26-mediated T cell activation have been extensively evaluated by our group and others, potential negative feedback mechanisms to regulate CD26-mediated activation still remain to be elucidated. In the present study, we examine the expression of inhibitory molecules induced via CD26-mediated costimulation. We show that coengagement of CD3 and CD26 induces preferential production of IL-10 in human CD4(+) T cells, mediated through NFAT and Raf-MEK-ERK pathways. A high level of early growth response 2 (EGR2) is also induced following CD26 costimulation, possibly via NFAT and AP-1-mediated signaling, and knockdown of EGR2 leads to decreased IL-10 production. Furthermore, CD3/CD26-stimulated CD4(+) T cells clearly suppress proliferative activity and effector cytokine production of bystander T cells in an IL-10-dependent manner. Taken together, our data suggest that robust CD26 costimulatory signaling induces preferential expression of EGR2 and IL-10 as a potential mechanism for regulating CD26-mediated activation.
authors.affiliation: Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan; Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; and.
authors.forename: Ryo
authors.initials: R
authors.lastname: Hatano
authors.affiliation: Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan;
authors.forename: Kei
authors.initials: K
authors.lastname: Ohnuma
authors.affiliation: Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan;
authors.forename: Haruna
authors.initials: H
authors.lastname: Otsuka
authors.affiliation: Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan;
authors.forename: Eriko
authors.initials: E
authors.lastname: Komiya
authors.affiliation: Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan;
authors.forename: Izumi
authors.initials: I
authors.lastname: Taki
authors.affiliation: Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan;
authors.forename: Satoshi
authors.initials: S
authors.lastname: Iwata
authors.affiliation: Division of Hematology/Oncology, University of Florida, Gainesville, FL 32610.
authors.forename: Nam H
authors.initials: NH
authors.lastname: Dang
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; and.
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.affiliation: Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan; morimoto@ims.u-tokyo.ac.jp.
authors.forename: Chikao
authors.initials: C
authors.lastname: Morimoto
mesh_terms: D016207:Cytokines / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D051767:Early Growth Response Protein 2 / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D056747:Immunomodulation; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000096:biosynthesis / Q000378:metabolism*; D008213:Lymphocyte Activation; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D048490:raf Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; D051767:Early Growth Response Protein 2; D050778:NFATC Transcription Factors; D016753:Interleukin-10; D048490:raf Kinases; D020928:Mitogen-Activated Protein Kinases; D018819:Dipeptidyl Peptidase 4