title: Hydrogen sulfide is an endogenous potentiator of T cell activation.
abstract: H(2)S is an endogenous signaling molecule that may act via protein sulfhydrylation to regulate various physiological functions. H(2)S is also a byproduct of dietary sulfate metabolism by gut bacteria. Inflammatory bowel diseases such as ulcerative colitis are associated with an increase in the colonization of the intestine by sulfate reducing bacteria along with an increase in H(2)S production. Consistent with its increased production, H(2)S is implicated as a mediator of ulcerative colitis both in its genesis or maintenance. As T cells are well established mediators of inflammatory bowel disease, we investigated the effect of H(2)S exposure on T cell activation. Using primary mouse T lymphocytes (CD3+), OT-II CD4+ T cells, and the human Jurkat T cell line, we show that physiological levels of H(2)S potentiate TCR-induced activation. Nanomolar levels of H(2)S (50-500 nM) enhance T cell activation assessed by CD69 expression, interleukin-2 expression, and CD25 levels. Exposure of T cells to H(2)S dose-dependently enhances TCR-stimulated proliferation with a maximum at 300 nM (30% increase, p < 0.01). Furthermore, activation increases the capacity of T cells to make H(2)S via increased expression of cystathionine γ-lyase and cystathionine β-synthase. Disrupting this response by silencing these H(2)S producing enzymes impairs T cell activation, and proliferation and can be rescued by the addition of 300 nM H(2)S. Thus, H(2)S represents a novel autocrine immunomodulatory molecule in T cells.
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Miller
authors.forename: Evelyn A
authors.initials: EA
authors.lastname: Wang
authors.forename: Serge
authors.initials: S
authors.lastname: Gould
authors.forename: Erica V
authors.initials: EV
authors.lastname: Stein
authors.forename: Sukhbir
authors.initials: S
authors.lastname: Kaur
authors.forename: Langston
authors.initials: L
authors.lastname: Lim
authors.forename: Shoba
authors.initials: S
authors.lastname: Amarnath
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Fowler
authors.forename: David D
authors.initials: DD
authors.lastname: Roberts
mesh_terms: D000393:Air Pollutants / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000276:immunology; D003542:Cystathionine gamma-Lyase / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006801:Humans; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D019169:Jurkat Cells; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D000099192:CD69 Antigens
chemical_list: D000393:Air Pollutants; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D037181:Lectins, C-Type; D000099192:CD69 Antigens; C508594:IL2 protein, human; C508017:IL2RA protein, human; C508018:Il2ra protein, mouse