title: Hematopoietic stem and multipotent progenitor cells produce IL-17, IL-21 and other cytokines in response to TLR signals associated with late apoptotic products and augment memory Th17 and Tc17 cells in the bone marrow of normal and lupus mice.
abstract: We studied effects of early and late apoptotic (necroptotic) cell products, related damage associated alarmins and TLR agonists, on hematopoietic stem and progenitor cells (HSPC). Surprisingly, normal HSPC themselves produced IL-17 and IL-21 after 1½days of stimulation, and the best stimulators were TLR 7/8 agonist; HMGB1-DNA; TLR 9 agonist, and necroptotic B cells. The stimulated HSPC expressed additional cytokines/mediators, directly causing rapid expansion of IL-17(+) memory CD4 T (Th17), and CD8 T (Tc17) cells, and antigen-experienced IL-17(+) T cells with "naïve" phenotype. In lupus marrow, HSPC were spontaneously pre-stimulated by endogenous signals to produce IL-17 and IL-21. In contrast to HSPC, megakaryocyte progenitors (MKP) did not produce IL-17, and unlike HSPC, they could process and present particulate apoptotic autoantigens to augment autoimmune memory Th17 response. Thus abnormally stimulated primitive hematopoietic progenitors augment expansion of IL-17 producing immune and autoimmune memory T cells in the bone marrow, which may affect central tolerance.
authors.affiliation: Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Ching-I
authors.initials: CI
authors.lastname: Chen
authors.affiliation: Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: skd257@northwestern.edu.
authors.forename: Syamal K
authors.initials: SK
authors.lastname: Datta
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001853:Bone Marrow / Q000276:immunology*; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D016207:Cytokines / Q000276:immunology*; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology; D007378:Interleukins / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology*; D051379:Mice; D039902:Multipotent Stem Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D051193:Toll-Like Receptors; D000098546:Interleukin-21
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D016207:Cytokines; C508717:IL17A protein, human; D020381:Interleukin-17; D007378:Interleukins; D051193:Toll-Like Receptors; D000098546:Interleukin-21
keywords: Apoptosis; Bone marrow; Cytokines; Hematopoietic progenitors; Lupus; Memory Th17/Tc17 cells; TLR signals