CD1d-unrestricted NKT cells are endowed with a hybrid function far superior than that of iNKT cells.

Invariant natural killer T (iNKT) cells to date represent the best example of cells known to have a hybrid function, representing both innate and adaptive immunity. Shared phenotypic similarities with NK cells together with a rapid response to a cytokine stimulus and a productive TCR engagement are the features that underline the hybrid nature of iNKT cells. Using these criteria, we provide molecular and functional evidence demonstrating that CD1d-independent (CD1d(ind)) NKT cells, a population of CD1d-unrestricted NKT cells, are endowed with a hybrid function far superior to that of iNKT cells: (i) an extensive shared program with NK cells, (ii) a closer Euclidian distance with NK cells, and (iii) the ability to respond to innate stimuli (Poly:IC) with cytotoxic potential in the same manner as NK cells identify a hybrid feature in CD1d(ind)NKT cells that truly fulfills the dual function of an NK and a T cell. Our finding that CD1d(ind)NKT cells are programmed to act like NK cells in response to innate signals while being capable of adaptive responses is unprecedented, and thus might reemphasize CD1d-unrestricted NKT cells as a subset of lymphocytes that could affect biological processes of antimicrobial and tumor immunity in a unique way.

TGF-ß signaling initiated in dendritic cells instructs suppressive effects on Th17 differentiation at the site of neuroinflammation.

While the role of Transforming Growth Factor ß (TGF-ß) as an intrinsic pathway has been well established in driving de novo differentiation of Th17 cells, no study has directly assessed the capacity of TGF-ß signaling initiated within dendritic cells (DCs) to regulate Th17 differentiation. The central finding of this study is the demonstration that Th17 cell fate during autoimmune inflammation is shaped by TGF-ß extrinsic pathway via DCs. First, we provide evidence that TGF-ß limits at the site of inflammation the differentiation of highly mature DCs as a means of restricting Th17 cell differentiation and controlling autoimmunity. Second, we demonstrate that TGF-ß controls DC differentiation in the inflammatory site but not in the priming site. Third, we show that TGF-ß controls DC numbers at a precursor level but not at a mature stage. While it is undisputable that TGF-ß intrinsic pathway drives Th17 differentiation, our data provide the first evidence that TGF-ß can restrict Th17 differentiation via DC suppression but such a control occurs in the site of inflammation, not at the site of priming. Such a demarcation of the role of TGF-ß in DC lineage is unprecedented and holds serious implications vis-à-vis future DC-based therapeutic targets.

TGF-ß is responsible for NK cell immaturity during ontogeny and increased susceptibility to infection during mouse infancy.

A large gap in our understanding of infant immunity is why natural killer (NK) cell responses are deficient, which makes infants more prone to viral infection. Here we demonstrate that transforming growth factor-ß (TGF-ß) was responsible for NK cell immaturity during infancy. We found more fully mature NK cells in CD11c(dnR) mice, whose NK cells lack TGF-ß receptor (TGF-ßR) signaling. Ontogenic maturation of NK cells progressed faster in the absence of TGF-ß signaling, which results in the formation of a mature NK cell pool early in life. As a consequence, infant CD11c(dnR) mice efficiently controlled viral infections. These data thus demonstrate an unprecedented role for TGF-ß in ontogeny that can explain why NK cell responses are deficient early in life.

Increased total cytokeratin-18 serum and urine levels in chronic kidney disease.

BACKGROUND: Increased cell death in chronic kidney disease (CKD) by either necrosis or apoptosis has been confirmed by a variety of studies. Possible sources are an inadequate persistent inflammation and ischemia as a consequence of CKD or caused by the underlying renal disease. Detection of total or caspase cleaved cytokeratin 18 (CK-18) is a novel and elegant method to determine necrosis or apoptosis of epithelial cells in the patients' sera and urine. METHODS: 120 patients with CKD stages 1 to 5 were included in the study. Twenty healthy volunteers served as controls. Total and caspase cleaved CK-18 urine and serum concentrations were determined by ELISA. RESULTS: The concentration of serum total CK-18 was significantly higher in CKD stages 3-5 as compared to the healthy controls. Urinary total CK-18 excretion was increased in patients with CKD 5 compared to controls. A significant correlation between urine total CK18 and urine protein and albumin levels was found. Moreover, ROC curve analysis showed the potential of serum and especially urine total CK-18 levels to predict various CKD stages. CONCLUSIONS: We provide evidence for increased total CK-18 serum and urine levels in CKD patients, possibly indicating that epithelial cell necrosis is prevalent in CKD.