title: Chromatin decondensation and T cell hyperresponsiveness in diabetes-associated hyperglycemia.
abstract: Diabetes is linked to increased inflammation and susceptibility to certain infectious diseases including tuberculosis (TB). We previously reported that aerosol TB in mice with chronic (≥ 12 wk) hyperglycemia features increased bacterial load, overproduction of several cytokines, and increased immune pathology compared with normoglycemic controls. A similar phenotype exists in human patients with diabetes with TB. The mechanisms of increased T cell activation in diabetes are unknown. In the current study, we tested the hypothesis that hyperglycemia modifies the intrinsic responsiveness of naive T cells to TCR stimulation. Purified T cells from chronically hyperglycemic (HG) mice produced higher levels of Th1, Th2, and Th17 cytokines and proliferated more than T cells from normoglycemic controls after anti-CD3e or Ag stimulation. In this way, naive T cells from HG mice resembled Ag-experienced cells, although CD44 expression was not increased. Chromatin decondensation, another characteristic of Ag-experienced T cells, was increased in naive T cells from HG mice. That phenotype depended on expression of the receptor for advanced glycation end products and could be reversed by inhibiting p38 MAPK. Chromatin decondensation and hyperresponsiveness to TCR stimulation persisted following transfer of T cells from HG mice into normoglycemic mice. We propose that chronic hyperglycemia causes receptor for advanced glycation end products-mediated epigenetic modification of naive T cells leading to p38 MAPK-dependent chromatin decondensation. This preactivation state facilitates transcription factor access to DNA, increasing cytokine production and proliferation following TCR stimulation. This mechanism may contribute to pathological inflammation associated with diabetes and might offer a novel therapeutic target.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655; and.
authors.forename: Nuria
authors.initials: N
authors.lastname: Martinez
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655; and.
authors.forename: Therese
authors.initials: T
authors.lastname: Vallerskog
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655; and.
authors.forename: Kim
authors.initials: K
authors.lastname: West
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655.
authors.forename: Claudio
authors.initials: C
authors.lastname: Nunes-Alves
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655; and.
authors.forename: Jinhee
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655; and.
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Martens
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655.
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Behar
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655; and Hardy.Kornfeld@umassmed.edu.
authors.forename: Hardy
authors.initials: H
authors.lastname: Kornfeld
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D003920:Diabetes Mellitus / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism; D006943:Hyperglycemia / Q000235:genetics* / Q000276:immunology*; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000276:immunology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism
chemical_list: D002843:Chromatin; D016207:Cytokines; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic