CD39 and CD161 Modulate Th17 Responses in Crohn's Disease

Abstract

CD39 (ENTPD1) is expressed by subsets of pathogenic human CD4+ T cells, such as T helper type 17 (Th17) cells. These Th17 cells are considered important in intestinal inflammation, such as seen in Crohn’s disease. Recently, CD161 (NKR-P1A) has been shown to be a phenotypic marker of human Th17 cells. In this study, we report that co-expression of CD161 and CD39 not only identifies these cells but also promotes Th17 generation. We note that human CD4+CD39+CD161+ T cells can be induced under stimulatory conditions that promote Th17 in vitro. Furthermore, CD4+CD39+CD161+ cells purified from blood and intestinal tissues, from both healthy controls and patients with Crohn’s disease, are of the Th17 phenotype and exhibit pro-inflammatory functions. CD39 is co-expressed with CD161, and this association augments acid sphingomyelinase (ASM) activity upon stimulation of CD4+ T cells. These pathways regulate mTOR and STAT3 signaling to drive the Th17 phenotype. Inhibition of ASM activity by pharmacological blockers or knockdown of ASM abrogates STAT3 signaling, thereby limiting IL-17 production in CD4+ T cells obtained from both controls and patients with active Crohn’s disease. Increased levels of CD39+CD161+ CD4+ T cells in blood or lamina propria are noted in patients with Crohn’s disease; and levels directly correlate with clinical disease activity. Hence, co-expression of CD39 and CD161 by CD4+ T cells might serve as a biomarker to monitor Th17 responsiveness. Collectively, CD39 and CD161 modulate human Th17 responses in Crohn's disease through alterations in purinergic nucleotide-mediated responses and ASM catalytic bioactivity, respectively.

Beyond ecto-nucleotidase: CD39 defines human Th17 cells with CD161

“…We also show that blood and lamina propria levels of CD39 + CD161 + CD4 + T cells reflect the disease activity of Crohn's disease [7]. These findings support the notion of CD4 + CD39 + CD161 + T cells perhaps developing as Th17 precursors, and expanding further to proinflammatory Th17 cells at sites of disease, as in patients with Crohn's disease.…”

“…Recently, we suggest that dual expression of CD39 and CD161 better defines Th17 lineages of human CD4 + T cells [7]. We also show that blood and lamina propria levels of CD39 + CD161 + CD4 + T cells reflect the disease activity of Crohn's disease [7].…”

“…This change was concomitant with sustained activation of STAT3 and mTOR signals [7]. However, inhibition of ASM activity in CD4 + T cells by ASM inhibitors or knockdown of ASM substantially abrogated ceramide generation and subsequently blocked STAT3 and mTOR activation, which consequently inhibited IL-17 + cell induction/expansion [7]. These results indicate that ASM activity is the upstream of STAT3 and mTOR, the integral components of Th17 generation.…”

“…We have further confirmed that in human CD4 + T cells, ASM directly interacts with CD39 and CD161, respectively. Upon activation, both stimulations of CD39 and CD161 by crosslinked antibodies can initiate ASM enzymatic activity, increase cellular ceramide production, and impact downstream signaling components of STAT3 and mTOR [7], which are the indispensible elements for Th17 generation [1].…”

“…Production of ceramide by CD4 + T cells was dramatically induced under Th17 polarization conditions. This change was concomitant with sustained activation of STAT3 and mTOR signals [7]. However, inhibition of ASM activity in CD4 + T cells by ASM inhibitors or knockdown of ASM substantially abrogated ceramide generation and subsequently blocked STAT3 and mTOR activation, which consequently inhibited IL-17 + cell induction/expansion [7].…”