Person:

Quintana, Francisco

Inflammasomes are multi-protein complexes that control the production of pro-inflammatory cytokines such as IL-1β. Inflammasomes play an important role in the control of immunity to tumors and infections, and also in autoimmune diseases, but the mechanisms controlling the activation of human inflammasomes are largely unknown. We found that human activated CD4+CD45RO+ memory T-cells specifically suppress P2X7R-mediated NLRP3 inflammasome activation, without affecting P2X7R-independent NLRP3 or NLRP1 inflammasome activation. The concomitant increase in pro-IL-1β production induced by activated memory T-cells concealed this effect. Priming with IFNβ decreased pro-IL-1β production in addition to NLRP3 inflammasome inhibition and thus unmasked the inhibitory effect on NLRP3 inflammasome activation. IFNβ suppresses NLRP3 inflammasome activation through an indirect mechanism involving decreased P2X7R signaling. The inhibition of pro-IL-1β production and suppression of NLRP3 inflammasome activation by IFNβ-primed human CD4+CD45RO+ memory T-cells is partly mediated by soluble FasL and is associated with down-regulated P2X7R mRNA expression and reduced response to ATP in monocytes. CD4+CD45RO+ memory T-cells from multiple sclerosis (MS) patients showed a reduced ability to suppress NLRP3 inflammasome activation, however their suppressive ability was recovered following in vivo treatment with IFNβ. Thus, our data demonstrate that human P2X7R-mediated NLRP3 inflammasome activation is regulated by activated CD4+CD45RO+ memory T cells, and provide new information on the mechanisms mediating the therapeutic effects of IFNβ in MS.

T helper type 17 (Th17) lymphocytes, characterized by the production of interleukin-17 and other pro-inflammatory cytokines, are present in intestinal lamina propria and have been described as important players driving intestinal inflammation. Recent evidence, supporting the notion of a functional and phenotypic instability of Th17 cells, has shown that Th17 differentiate into type 1 regulatory (Tr1) T cells during the resolution of intestinal inflammation. Moreover, it has been suggested that the expression of CD39 ectonucleotidase endows Th17 cells with immunosuppressive properties. However, the exact role of CD39 ectonucleotidase in Th17 cells has not been studied in the context of intestinal inflammation. Here we show that Th17 cells expressing CD39 ectonucleotidase can hydrolyze ATP and survive to ATP-induced cell death. Moreover, in vitro-generated Th17 cells expressing the CD39 ectonucleotidase produce IL-10 and are less pathogenic than CD39 negative Th17 cells in a model of experimental colitis in Rag-/- mice. Remarkably, we show that CD39 activity regulates the conversion of Th17 cells to IL-10-producing cells in vitro, which is abrogated in the presence of ATP and the CD39-specific inhibitor ARL67156. All these data suggest that CD39 expression by Th17 cells allows the depletion of ATP and is crucial for IL-10 production and survival during the resolution of intestinal inflammation.

Induced regulatory T-cells (iT-reg) and T helper type 17 (Th17) in the mouse share common CD4 progenitor cells and exhibit overlapping phenotypic and functional features. Here, we show that human Th17 cells endowed with suppressor activity (supTh17) can be derived following exposure of iT-reg populations to Th17 polarizing conditions. In contrast to “pathogenic” Th17, supTh17 display immune suppressive function and express high levels of CD39, an ectonucleotidase that catalyzes the conversion of pro-inflammatory extracellular nucleotides ultimately generating nucleosides. Accordingly, supTh17 exhibit nucleoside triphosphate diphosphohydrolase activity, as demonstrated by the efficient generation of extracellular AMP, adenosine and other purine derivatives. In addition supTh17 cells are resistant to the effects of adenosine as result of the low expression of the A2A receptor and accelerated adenosine catalysis by adenosine deaminase (ADA). These supTh17 can be detected in the blood and in the lamina propria of healthy subjects. However, these supTh17 cells are diminished in patients with Crohn’s disease. In summary, we describe a human Th17 subpopulation with suppressor activity, which expresses high levels of CD39 and consequently produces extracellular adenosine. As these uniquely suppressive CD39+ Th17 cells are decreased in patients with inflammatory bowel disease, our findings might have implications for the development of novel anti-inflammatory therapeutic approaches in these and potentially other immune disorders.