Role of regulatory T cells in neutrophil function

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• 作者：Dr Andrew Conway Morris ; PhD^a ; ^{ac926@cam.ac.uk" class="auth_mail" title="E-mail the corresponding author} ; Jillian Rennie ; BSc^b ; Prof Adriano G Rossi ; PhD^b ; Prof Timothy S Walsh ; MD^b
• 刊名：The Lancet
• 出版年：2016
• 出版时间：25 February 2016
• 年：2016
• 卷：387
• 期：supp_S1
• 页码：S30
• 全文大小：50 K

文摘

In systemic inflammatory response syndromes such as sepsis, there is an apparently paradoxical finding of impaired immune cell function. We have previously identified dysfunctional neutrophils and elevated proportions of regulatory T cells (Tregs) as predictors of nosocomial infection. Whether synergistic effects exist between neutrophils and Tregs is unclear. This study aimed to examine whether Tregs could impair neutrophil function, and what mechanisms could underpin any effect.

Methods

Healthy human donor leucocytes were extracted from whole blood, and Tregs and T effector cells (Teffs) were purified with antibody-based selection. Tregs or Teffs were co-incubated with neutrophils before exposure to zymosan as the phagocytic target. Mechanism was explored through the use of membranes to separate T cells from neutrophils, T cell conditioned media, inhibitors of key downstream signalling pathways (adenylate cyclase and phosphoinositide 3-kinase [PI3K]), and purified E-type prostaglandins (PGE1 and PGE2).

Findings

Tregs were able to suppress phagocytosis by neutrophils, an effect that was not seen with Teffs. This effect was mediated by a soluble mediator and could be prevented by incubation of Tregs with inhibitors of cyclo-oxygenase and blockade of EP4, but not EP2, receptors. The effects of Tregs were also prevented by inhibition of adenylate cyclase and PI3Kδ. These effects could be recapitulated with use of purified PGE1 and PGE2, which also acted via the EP4 receptor, adenylate cyclase, and PI3Kδ. Although Tregs impaired generation of neutrophil reactive oxygen species, this effect did not appear to be mediated via the same pathway.

Interpretation

This study shows that, in vitro, Tregs can impair the key neutrophil function of phagocytosis. This process appears to be mediated through secretion of E-type prostaglandins, which act through adenylate cyclase and PI3Kδ. This finding sheds new light on the association between elevated Tregs and nosocomial infection, and suggests potential targets for therapeutic intervention. The findings are restricted to in-vitro models, and will require further confirmation in vivo.

Funding

National Institute of Academic Anaesthesia.