title: Janus kinase-2 inhibition induces durable tolerance to alloantigen by human dendritic cell-stimulated T cells yet preserves immunity to recall antigen.
abstract: Janus kinase-2 (JAK2) conveys receptor-binding signals by several inflammatory cytokines, including IL-6, via phosphorylation of signal transducer and activator of transcription 3 (STAT3). We demonstrate that selective JAK2 inhibition by TG101348 during initial encounters between human T cells and allogeneic monocyte-derived dendritic cells induces durable, profound, and specific T-cell tolerance upon reexposure to the same alloantigens. Subsequent responses by nonalloreactive T cells to stimulation de novo by a pathogenic nominal antigen remain intact. TG101348 also suppresses primed T-cell responses when present only during alloantigen restimulation. TG101348 ablates IL-6/JAK2-mediated phosphorylation of STAT3, but has no off-target effects on IL-2 or IL-15/JAK3/pSTAT5-dependent signaling, which sustain the responses of regulatory T cells (Tregs) and other effector T cells. JAK2 inhibition preserves Treg numbers and thereby enhances the ratio of CD4(+) Tregs to CD8(+)CD25(+) effector T cells in favor of Tregs. JAK2 inhibition also reduces the production of IL-6 and TNF-α in allogeneic MLRs, impairing the activation of central and effector memory T cells as well as the expansion of responder Th1 and Th17 cells. While we have reported the limitations of isolated IL-6R-α inhibition on dendritic cell-stimulated alloreactivity, we demonstrate here that JAK2 represents a relevant biologic target for controlling GVHD or allograft rejection without broader immune impairment.
authors.affiliation: Laboratory of Cellular Immunobiology, Immunology Program, Sloan-Kettering Institute for Cancer Research, New York, NY 10065, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Betts
authors.forename: Omar
authors.initials: O
authors.lastname: Abdel-Wahab
authors.forename: Shane A
authors.initials: SA
authors.lastname: Curran
authors.forename: Erin T
authors.initials: ET
authors.lastname: St Angelo
authors.forename: Priya
authors.initials: P
authors.lastname: Koppikar
authors.forename: Glenn
authors.initials: G
authors.lastname: Heller
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: James W
authors.initials: JW
authors.lastname: Young
mesh_terms: D002454:Cell Differentiation; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D007156:Immunologic Memory; D066298:In Vitro Techniques; D007519:Isoantigens; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D011759:Pyrrolidines / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D013449:Sulfonamides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D000096926:Benzenesulfonamides
chemical_list: D016207:Cytokines; D007519:Isoantigens; D053614:Janus Kinase 2; D011759:Pyrrolidines; D013449:Sulfonamides; C528327:fedratinib; D000096926:Benzenesulfonamides; C507924:JAK2 protein, human