title: Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease.
abstract: A major function of NKG2D linking innate and adaptive immunity is to upregulate antigen-specific CTL-mediated cytotoxicity in tissues expressing stress-induced NKG2D ligands, such as MIC, by coactivating TCR signaling. Here, we show that, under conditions of dysregulated IL15 expression in vivo in patients with celiac disease and in vitro in healthy individuals, multiple steps of the NKG2D/DAP10 signaling pathway leading to ERK and JNK activation are coordinately primed to activate direct cytolytic function independent of TCR specificity in effector CD8 T cells. These findings may not only explain previous reports of transformation of CTL into NK-like "lymphokine-activated killers" (LAK cells) under high doses of IL2 (a substitute for IL15) but may also have significant implications for understanding and treating immunopathological diseases.
authors.affiliation: Department of Pathology, University of Chicago, IL 60637, USA.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Meresse
authors.forename: Zhangguo
authors.initials: Z
authors.lastname: Chen
authors.forename: Cezary
authors.initials: C
authors.lastname: Ciszewski
authors.forename: Maria
authors.initials: M
authors.lastname: Tretiakova
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Krausz
authors.forename: David H
authors.initials: DH
authors.lastname: Raulet
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Lanier
authors.forename: Veronika
authors.initials: V
authors.lastname: Groh
authors.forename: Thomas
authors.initials: T
authors.lastname: Spies
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Ebert
authors.forename: Peter H
authors.initials: PH
authors.lastname: Green
authors.forename: Bana
authors.initials: B
authors.lastname: Jabri
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002446:Celiac Disease / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D019409:Interleukin-15 / Q000276:immunology* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011971:Receptors, Immunologic / Q000276:immunology* / Q000378:metabolism; D055607:Receptors, Natural Killer Cell; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D019409:Interleukin-15; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011948:Receptors, Antigen, T-Cell; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell