Helicobacter pyloriγ-glutamyltranspeptidase impairs T-lymphocyte function by compromising metabolic adaption through inhibition of cMyc and IRF4 expression

Abstract

SummaryHelicobacter pylori (H. pylori) is a humanspecific pathogen that has evolved to cope with the immune response elicited against the infection. We previously reported that H. pylori γ-glutamyltranspeptidase (gGT) impairs T-lymphocyte proliferation and thus might act as immune regulatory factor. In this study, we analysed the underlying mechanism and its implications for H. pylori persistence. We found that H. pylori gGT compromised T-cell proliferation, activation and effector cytokine expression by specifically depriving the extracellular space of glutamine. When assessing signalling cascades and transcription factors affected by H. pylori gGT, we found that expression of cMyc and IRF4, both required for metabolic adaptation of T-lymphocytes, was highly sensitive to extracellular glutamine levels and downregulated upon gGT treatment. Moreover, we could confirm decreased IRF4 expression in T-lymphocytes infiltrating the stomach of infected individuals. Thus, our results suggest that H. pylori gGT-mediated glutamine deprivation in the gastric mucosa may suppress T-cell function thereby contributing to bacterial persistence.

Helicobacter pylori γ-Glutamyltranspeptidase Induces Tolerogenic Human Dendritic Cells by Activation of Glutamate Receptors

“…Specifically, we examined the effects of glutamine and glutamate, substrate and product, respectively, of the hydrolysis reaction catalyzed by gGT. In contrast to the high sensitivity to glutamine depletion due H. pylori gGT observed in T cells (1), glutamine deprivation did not have major effects on DCs. Thus, neither alterations in the maturation status of DCs nor changes in cytokine secretion and subsequent T cell differentiation were detected as a result of glutamine depletion.…”

“…Among those, H. pylori gGT has been linked to immune evasion by blocking T cell proliferation and function (1,17), whereas in murine models of infection, gGT was reported to induce tolerance by reprogramming DCs toward a tolerogenic phenotype (6). In the current study, we have analyzed whether H. pylori gGT shows the same immunomodulatory effects on human DCs.…”

Systems-wide analyses of mucosal immune responses toHelicobacter pyloriat the interface between pathogenicity and symbiosis

“…124 H. pylori g-glutamyltranspeptidase depletes extracellular glutamine and consequently inhibits T lymphocyte proliferation, impairs activation and inhibits cytokine secretion involving IRF4. 125 Endocytosis of VacA into activated human primary T cells 126 inhibits cell proliferation and the clonal expansion of H. pylori antigen specific T-cells. 127 It has also been shown that VacA can block T cell activation by preventing influx of extracellular calcium and subsequent nuclear translocation of NF-AT and by stimulating disordered actin polymerization through Rac activation.…”

Pathogenesis of Helicobacter pylori Infection

“…Helicobacter pylori persistence has also been demonstrated to be favored by the activity of gGT, which has been demonstrated to impair T‐cell proliferation . More specifically, Wüstner et al.…”