title: Identification and characterization of distinct IL-17F expression patterns and signaling pathways in chronic lymphocytic leukemia and normal B lymphocytes.
abstract: Chronic lymphocytic leukemia (CLL) is characterized by a progressive accumulation of B lymphocytes. T cell abnormalities are a common feature of CLL and contribute to impaired immune function in these patients. T cells are ineffective in eliminating the leukemic clone and may actually promote tumor growth and survival. Previous work from our laboratory documented elevated circulating levels of IL-17A-producing Th17 cells in CLL patients as compared to healthy age-matched control subjects. These high circulating Th17 levels associated with better prognostic markers and significantly longer overall survival, even among patients whose clones used unmutated IGHVs (U-CLL). Recent studies suggest that Th17 cells are heterogeneous, expressing different profiles of cytokines, and that different subsets of Th17s mediate different biological functions. In the present study, we found significantly higher levels of IL-17F-expressing CD4(+) T cells in CLL versus healthy peripheral blood mononuclear cells following in vitro stimulation in the presence of Th17-promoting cytokines. Furthermore, the differentiation of IL-17F-expressing Th17 cells was significantly enhanced when purified CD4(+) T cells from CLL patients were cultured in the presence of autologous CLL B cells. Lastly, single-cell network profiling revealed that IL-17F triggers NFκB phosphorylation in T and B cells from patients with CLL, but not age-matched healthy controls. Taken together, our data suggest that the phenotype of Th17 cells in CLL patients is distinct from healthy individuals, expressing higher levels of IL-17F, and that B and T cells from CLL patients are particularly responsive to IL-17F, as compared to healthy age-matched control individuals.
authors.affiliation: Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA. BSherry@nshs.edu.|Department of Medicine, Hofstra North Shore-LIJ School of Medicine, Hofstra University, Hempstead, NY, USA. BSherry@nshs.edu.|Department of Molecular Medicine, Hofstra North Shore-LIJ School of Medicine, Hofstra University, Hempstead, NY, USA. BSherry@nshs.edu.
authors.forename: Barbara
authors.initials: B
authors.lastname: Sherry
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Internal Medicine, University of Texas Medical School at Houston, Houston, TX, USA.
authors.forename: Preetesh
authors.initials: P
authors.lastname: Jain
authors.affiliation: Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA.
authors.forename: Pui Yan
authors.initials: PY
authors.lastname: Chiu
authors.affiliation: Nodality, Inc., South San Francisco, CA, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Leung
authors.affiliation: Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, NY, USA.|Department of Medicine, Hofstra North Shore-LIJ School of Medicine, Hofstra University, Hempstead, NY, USA.|Department of Medicine, North Shore University Hospital and Long Island Jewish Medical Center, North Shore-LIJ Health System, Manhasset, NY, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Allen
authors.affiliation: Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, NY, USA.|Department of Medicine, Hofstra North Shore-LIJ School of Medicine, Hofstra University, Hempstead, NY, USA.|Department of Medicine, North Shore University Hospital and Long Island Jewish Medical Center, North Shore-LIJ Health System, Manhasset, NY, USA.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Kolitz
authors.affiliation: Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, NY, USA.|Department of Medicine, Hofstra North Shore-LIJ School of Medicine, Hofstra University, Hempstead, NY, USA.|Department of Medicine, North Shore University Hospital and Long Island Jewish Medical Center, North Shore-LIJ Health System, Manhasset, NY, USA.
authors.forename: Kanti R
authors.initials: KR
authors.lastname: Rai
authors.affiliation: Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, NY, USA.|Department of Medicine, Hofstra North Shore-LIJ School of Medicine, Hofstra University, Hempstead, NY, USA.|Department of Medicine, North Shore University Hospital and Long Island Jewish Medical Center, North Shore-LIJ Health System, Manhasset, NY, USA.
authors.forename: Jacquie
authors.initials: J
authors.lastname: Barrientos
authors.affiliation: Nodality, Inc., South San Francisco, CA, USA.
authors.forename: Spencer
authors.initials: S
authors.lastname: Liang
authors.affiliation: Nodality, Inc., South San Francisco, CA, USA.
authors.forename: Rachael
authors.initials: R
authors.lastname: Hawtin
authors.affiliation: Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, NY, USA.|Department of Medicine, Hofstra North Shore-LIJ School of Medicine, Hofstra University, Hempstead, NY, USA.|Department of Molecular Medicine, Hofstra North Shore-LIJ School of Medicine, Hofstra University, Hempstead, NY, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis* / Q000276:immunology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D015398:Signal Transduction; D058504:Th17 Cells / Q000276:immunology*; D059467:Transcriptome
chemical_list: D020381:Interleukin-17; D016328:NF-kappa B
keywords: Chronic Lymphocytic Leukemia (CLL); Interleukin-17 (IL-17); Th17 cells