Circulating and gut-resident human Th17 cells express CD161 and promote intestinal inflammation

Abstract

The C-type lectin-like receptor CD161, which has recently been described to promote T cell expansion, is expressed on a discrete subset of human CD4 T cells. The function of such cells, however, has remained elusive. We now demonstrate that CD161+ CD4 T cells comprise a circulating and gut-resident T helper 17 (Th17) cell population. During Crohn's disease (CD), these CD161+ cells display an activated Th17 phenotype, as indicated by increased expression of interleukin (IL)-17, IL-22, and IL-23 receptor. CD161+ CD4 T cells from CD patients readily produce IL-17 and interferon γ upon stimulation with IL-23, whereas, in healthy subjects, priming by additional inflammatory stimuli such as IL-1β was required to enable IL-23–induced cytokine release. Circulating CD161+ Th17 cells are imprinted for gut homing, as indicated by high levels of CC chemokine receptor 6 and integrin β7 expression. Supporting their colitogenic phenotype, CD161+ Th17 cells were found in increased numbers in the inflammatory infiltrate of CD lesions and induced expression of inflammatory mediators by intestinal cells. Our data identify CD161+ CD4 T cells as a resting Th17 pool that can be activated by IL-23 and mediate destructive tissue inflammation.

Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL‐22 and IL‐17 production by human T helper cells

“…6D). Finally, we assessed whether IL-22 single-positive cells generated in vitro from naïve T cells expressed CD161, a marker reported to be specific of Th17 cells [9,36]. Our results confirm the strong expression of CD161 by most IL-17 1 IL-22 À IFN-g À cells but also show that CD161 is virtually absent from IL-22 1 IL-17A À IFN-g À single-positive T cells (Fig.…”

“…Fifth, priming of CD4 1 naïve T cells in the presence of TCDD resulted in increased number of IL-22 1 IL-17 À IFN-g À single-positive T cells. Finally, CD161 selectively expressed in Th17 cells [9,36] was absent in IL-22 1 IL-17A À IFN-g À singlepositive T cells. Furthermore, our data regarding the dissociated IL-22 and IL-17 production are consistent with recent reports showing that skin-homing memory T cells [31,32], T cells present in the skin of individuals affected by atopic dermatitis [41], plaque psoriasis, allergic contact dermatitis [33] and T cells responding to mycobacteria [42] or Candida albicans [43] produce IL-22 but not IL-17A or IFN-g. Of interest, human Langerhans cells appear to favor the induction of CD4 1 T cells producing IL-22 but not IL-17, thus stressing a preferential role of these cells in skin immunosurveillance [44].…”

IL-7 Licenses Activation of Human Liver Intrasinusoidal Mucosal-Associated Invariant T Cells

“…For example, IL-1b increases the cell response to anti-CD3 stimulation and encourages maturation toward IL-17A production in CD161 + T cells (25). Similarly, conventional CD4 + T cells with a Th17 signature possess extended functional plasticity, and IL-7 (29,30) or a combination of IL-1b and IL-23 (31,32) may reduce the T cell-activation threshold and positively influence differentiation toward Th17 cells. Because Liv-MAIT cells produced high quantities of IL-17A only after mitogen stimulation, we tested whether inflammatory cytokines influence the maturation and responsiveness of Liv-MAIT cells to TCR-mediated stimulation.…”

Th17 cells: new players in asthma pathogenesis

“…Human Th17 cells are characterized by the expression of the transcription factor RAR-related orphan receptor C (RORC) (13), by the surface expression of IL-23 receptor (IL-23R), the chemokine receptor CCR6 (14,15), and the lectin receptor CD161, the orthologous of murine NK1.1 (16,17). Human Th17 cells originate from CD161+ CD4+ Tcell precursors, detectable in both human umbilical cord blood and thymus, when these cells are activated in presence of a combination of IL-1b and IL-23 (16).…”