Hydrogen Sulfide Is an Endogenous Potentiator of T Cell Activation*

Abstract

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 γ-lyase and cystathionine β-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.