Malefyt, René de Waal

Abstract Signaling lymphocyte activation molecule (Slamf1) is a T cell co-stimulatory molecule and a regulator of cytokine production by macrophages and dendritic cells. Because Slamf1 positively regulates microbicidal mechanisms in macrophages, we evaluate whether Slamf1 would affect enterocolitis. To induce colitis, mouse CD45RBhi CD4+ T cells were transferred into RAG-/- or Slamf1-/- RAG-/- recipient mice. In a second set of experiments, an agonistic αCD40 antibody was administered to the same recipient strains to induce colitis. Whilst the absence of Slamf1 in RAG-/- recipients mitigated colitis, the function of disease-causing effector or regulatory T cells was not affected by the ablation of the receptor. Surprisingly, in Slamf1-/- mice monocyte / macrophage migration into the inflamed tissue was impaired not only in αCD40-induced colitis but also in two other in vivo models of inflammation: thioglycolate induced peritonitis and in an “air pouch” model in response to TNFα. Administering αSlamf1 to RAG-/- mice ameliorated enterocolitis and altered this migration. Slamf1 is a key contributor to the innate immune responses during experimental colitis by affecting the migration of monocytes / macrophages to the sites of inflammation. As αSlamf1 also mitigates the pathogenesis of colitis, SLAMF1 should be a plausible therapeutic target in treating inflammatory bowel diseases.

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.