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.