Hydrogen sulfide (H2S) is an endogenous signaling molecule that may act via protein sulfhydrylation to regulate various physiological functions. H2S 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 H2S production. Consistent with its increased production, H2S 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 H2S 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 H2S potentiate TCR-induced activation. Nanomolar levels of H2S (50-500 nM) enhance T cell activation assessed by CD69 expression, interleukin-2 expression, and CD25 levels. Exposure of T cells to H2S 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 H2S via increased expression of cystathionine gamma-lyase and cystathionine beta-synthase. Disrupting this response by silencing these H2S producing enzymes impairs T cell activation, and proliferation and can be rescued by the addition of 300 nM H2S. Thus, H2S represents a novel autocrine immunomodulatory molecule in T cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIASC009174-24
Application #
8554030
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
24
Fiscal Year
2012
Total Cost
$423,296
Indirect Cost
Name
National Cancer Institute Division of Clinical Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Miller, Thomas W; Soto-Pantoja, David R; Schwartz, Anthony L et al. (2015) CD47 Receptor Globally Regulates Metabolic Pathways That Control Resistance to Ionizing Radiation. J Biol Chem 290:24858-74
Priya, Mani Krishna; Sahu, Giriraj; Soto-Pantoja, David R et al. (2015) Tipping off endothelial tubes: nitric oxide drives tip cells. Angiogenesis 18:175-89
Thomas, Douglas D; Heinecke, Julie L; Ridnour, Lisa A et al. (2015) Signaling and stress: The redox landscape in NOS2 biology. Free Radic Biol Med 87:204-25
Cook, Katherine L; Soto-Pantoja, David R; Abu-Asab, Mones et al. (2014) Mitochondria directly donate their membrane to form autophagosomes during a novel mechanism of parkin-associated mitophagy. Cell Biosci 4:16
Rogers, Natasha M; Seeger, Franziska; Garcin, Elsa D et al. (2014) Regulation of soluble guanylate cyclase by matricellular thrombospondins: implications for blood flow. Front Physiol 5:134
Navarathna, Dhammika H M L P; Munasinghe, Jeeva; Lizak, Martin J et al. (2013) MRI confirms loss of blood-brain barrier integrity in a mouse model of disseminated candidiasis. NMR Biomed 26:1125-34
Soto-Pantoja, David R; Stein, Erica V; Rogers, Natasha M et al. (2013) Therapeutic opportunities for targeting the ubiquitous cell surface receptor CD47. Expert Opin Ther Targets 17:89-103
Miller, Thomas W; Kaur, Sukhbir; Ivins-O'Keefe, Kelly et al. (2013) Thrombospondin-1 is a CD47-dependent endogenous inhibitor of hydrogen sulfide signaling in T cell activation. Matrix Biol 32:316-24
Miller, Thomas W; Wang, Evelyn A; Gould, Serge et al. (2012) Hydrogen sulfide is an endogenous potentiator of T cell activation. J Biol Chem 287:4211-21
Roberts, David D; Miller, Thomas W; Rogers, Natasha M et al. (2012) The matricellular protein thrombospondin-1 globally regulates cardiovascular function and responses to stress via CD47. Matrix Biol 31:162-9

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