The effector T-cell lineage shows great plasticity. Th17 cells are acknowledged to be instrumental in the response against microbial infection, but are also associated with autoimmune inflammatory processes. Here, we report that human regulatory T cells ( IntroductionIn mice, IL-17A (IL-17)-producing T cells have been established as an important T-helper (Th) effector lineage, clearly distinct from the Th1 or Th2 lineage. 1,2 Infectious disease mouse models indicate that IL-17-producing cells (Th17) mediate protection against extracellular pathogens. 3-5 However, on the downside, Th17 cells also appear to be the driving force in the pathogenesis of several autoimmune diseases. 2,6 Furthermore, mouse studies showed that differentiation of Th17 cells from naive CD4 T cells requires the concomitant activity of IL-6 and transforming growth factor-␤ (TGF␤). [7][8][9] The key transcription factor driving Th17 cell differentiation is the orphan nuclear receptor ROR␥t, which is needed for constitutive expression of In in vivo studies in mice, IL-17-and ROR␥t-expressing cells were shown to be present in the lung and digestive mucosal compartments, 11 and especially throughout the intestinal lamina propria. 10 In humans, IL-17 is associated with many inflammatory disorders such as rheumatoid arthritis, asthma, multiple sclerosis, lupus, Crohn disease, and allograft rejection. 3,[12][13][14][15] Recently, human ROR␥t-positive IL-17-producing T cells were identified under physiologic conditions in peripheral blood and tonsils, [15][16][17] being contained within the CCR6 ϩ (CCR4 ϩ )CD4 ϩ memory T-cell population. 15,16 Most recent data show that human Th17 differentiation, distinct from mouse Th17 development, is under control of IL-1␤, 19 In mice, the development of Th17 cells was described to be linked to that of regulatory T cells (Tregs) in a reciprocal fashion, whereby under the influence of TGF␤, IL-6 levels determine the outcome. 8,9 In vitro, activated Tregs promoted Th17 cell differentiation from CD4 T cells, 9,20 likely through their production of TGF␤.In addition, in vivo the transfer of Treg enhanced IL-17 production in a mouse model of systemic autoimmune disease. 21 Next, to this reciprocal relationship, it was recently demonstrated that IL-17-producing cells directly develop from mouse Tregs. 20 This is a remarkable finding, because Tregs are typically associated with T-cell tolerance and immune homeostasis. 22 Different Treg subsets have been described, and even within the naturally occurring CD4 pos CD25 high Foxp3 pos population heterogeneity is evident. This heterogeneity reflects differences in differentiation or developmental stage, trafficking properties, and suppressor capacity. [23][24][25] Although the lineage differentiation of helper T cells is very well accepted, that of Tregs is only scarcely recognized. In humans, naive and memory-like CD4 pos CD25 pos Foxp3 pos Treg have been defined in peripheral blood, discriminated by the expression of CD45 isoforms CD45RA and CD45RO. [25][26][27][28] Al...

Psoriasis is a common inflammatory skin disease with a prevalence of 2% to 3% in Caucasians1. In a genome-wide search for copy number variants (CNV) using a sample pooling approach we have identified a deletion comprising LCE3B and LCE3C, members of the late cornified envelope (LCE) gene cluster2. The absence of LCE3B and LCE3C (LCE3C-LCE3B-del) is significantly associated (p=1.38E-08) with risk of psoriasis in 2,831 samples from Spain, The Netherlands, Italy and the USA, and in a family-based study (p=5.4E-04). LCE3C-LCE3B-del is tagged by rs4112788 (r2=0.93), which is also strongly associated with psoriasis (p<6.6E-09). LCE3C-LCE3B-del shows epistatic effects with the HLA-Cw6 allele on the development of psoriasis in Dutch samples, and multiplicative effects in the other samples. LCE expression can be induced in normal epidermis by skin barrier disruption and is strongly expressed in psoriatic lesions, suggesting that compromised skin barrier function plays a role in psoriasis susceptibility.

Summary Differences in susceptibility to immune-mediated diseases are determined by variability in immune responses. In three studies within the Human Functional Genomics Project we assessed the effect of environmental and non-genetic host factors, of the genetic make-up of the host, and of the intestinal microbiome, on the cytokine responses in humans. We analyzed the association of these factors with circulating mediators and with six cytokines after stimulation with 19 bacterial, fungal, viral and non-microbial metabolic stimuli in 534 healthy subjects. In this first study we show a strong impact of non-genetic host factors (e.g. age and gender) on cytokine production and circulating mediators. Additionally, annual seasonality is found to be an important environmental factor influencing cytokine production. Alpha-1-antitrypsin concentrations partially mediate the seasonality of cytokine responses, whereas the effect of vitamin D levels is limited. The complete dataset has been made publicly available as a comprehensive resource for future studies.

Psoriasis is an autoimmune-related chronic inflammatory skin disease that is strongly associated with IL-23 and T helper-17 (Th17) effector cytokines. In addition, CD4+CD25(high) regulatory T-cell (Treg) function appeared to be impaired in psoriasis. CD4+CD25(high)Foxp3+ Tregs are typically considered inhibitors of autoimmune responses. However, under proinflammatory conditions, Tregs can differentiate into inflammation-associated Th17 cells--a paradigm shift, with as yet largely unknown consequences for human disease initiation or progression. Th17 cells are highly proinflammatory T cells that are characterized by IL-17A and IL-22 production and expression of the transcription factor retinoic acid-related orphan receptor γt (RORγt). We here show that Tregs of patients with severe psoriasis, as compared with those of healthy controls, have an enhanced propensity to differentiate into IL-17A-producing cells on ex vivo stimulation. This enhanced Treg differentiation was linked to unexpectedly high RORγt levels and enhanced loss of Foxp3. Notably, IL-23 boosted this Treg differentiation process particularly in patients with psoriasis but less so in controls. IL-23 further reduced Foxp3 expression while leaving the high RORγt levels unaffected. The histone/protein deacetylase inhibitor, Trichostatin-A, prevented Th17 differentiation of Tregs in psoriasis patients. Importantly, IL-17A+/Foxp3+/CD4+ triple-positive cells were present in skin lesions of patients with severe psoriasis. These data stress the clinical relevance of Treg differentiation for the perpetuation of chronic inflammatory disease and may pave novel ways for immunotherapy.

Signaling from endosomes is emerging as a mechanism by which selected receptors provide sustained signals distinct from those generated at the plasma membrane. The activity of natural killer (NK) cells, which are important effectors of innate immunity and regulators of adaptive immunity, is controlled primarily by receptors that are at the cell surface. Here we show that cytokine secretion by resting human NK cells is induced by soluble, but not solid-phase, antibodies to the killer cell immunoglobulin-like receptor (KIR) 2DL4, a receptor for human leukocyte antigen (HLA)-G. KIR2DL4 was constitutively internalized into Rab5-positive compartments via a dynamin-dependent process. Soluble HLA-G was endocytosed into KIR2DL4–containing compartments in NK cells and in 293T cells transfected with KIR2DL4. Chemokine secretion induced by KIR2DL4 transfection into 293T cells occurred only with recombinant forms of KIR2DL4 that trafficked to endosomes. The profile of genes up-regulated by KIR2DL4 engagement on resting NK cells revealed a proinflammatory/proangiogenic response. Soluble HLA-G induced secretion of a similar set of cytokines and chemokines. This unique stimulation of resting NK cells by soluble HLA-G, which is endocytosed by KIR2DL4, implies that NK cells may provide useful functions at sites of HLA-G expression, such as promotion of vascularization in maternal decidua during early pregnancy.