> Despite psoriasis being a common skin disease, there are still a number of unanswered questions. One of these is the prevalence of the disease, as there is a lack of specific data, with the majority of studies reporting estimates only. Population based studies are rare and longitudinal observations on changing prevalence rates are lacking. This contrasts with other T-cell mediated autoimmune diseases where the number of those affected is rising.

> NK1.1 + α βTCR + (NKT) cells have several important roles including tumor rejection and prevention of autoimmune disease. Although both CD4 + and CD4 – CD8 – double-negative (DN) subsets of NKT cells have been identified, they are usually described as one population. Here, we show that NKT cells are phenotypically, functionally and developmentally heterogeneous, and that three distinct subsets (CD4 + , DN and CD8 + ) are differentially distributed in a tissue-specific fashion. CD8 + NKT cells are present in all tissues but the thymus, and are highly enriched for CD8α + β – cells. These subsets differ in their expression of a range of cell surface molecules (Vβ8, DX5, CD69, CD45RB, Ly6C) and in their ability to produce IL-4 and IFN-γ, with splenic NKT cell subsets producing lower levels than thymic NKT cells. Developmentally, most CD4 + and DN NKT cells are thymus dependent, in contrast to CD8 + NKT cells, and are also present amongst recent thymic emigrants in spleen and liver. TCR Jα281-deficient mice show a dramatic deficiency in thymic NKT cells, whereas a significant NKT cell population (enriched for the DN and CD8 + subsets) is still present in the periphery. Taken together, this study reveals a far greater level of complexity within the NKT cell population than previously recognized.

Abstract NKT cells utilize a restricted αβ TCR repertoire that recognizes glycolipids in association with CD1d. The recent development of fluorescent CD1d tetramers loaded with the synthetic glycolipid α-galactosyl-ceramide has led to a clearer definition of NKT-cell subsets as well as important insights into their developmental origin. As many as four subsets may exist, differing in NK1.1 expression, TCR repertoire and dependence on CD1d and various glycolipids for development. Two different lineage-commitment models have been proposed, with most evidence favoring a byproduct of conventional-T-cell development.

Down-regulation of immune responses by regulatory T cells is one of the major mechanisms involved in the induction of tolerance to self- and alloantigens as demonstrated in a number of models of transplantation and autoimmunity. It is clear that regulatory T cells consist of different subsets. Recently a novel subset of antigen-specific αβ-TCR + CD4 – CD8 – (double negative, DN) regulatory T cells has been found to be able to inhibit the function of the CD8 + T cells carrying the same T cell receptor specificity and prevent the rejection of skin allografts. Identification of the DN regulatory T cells and their novel mechanism of suppression can help us to understand how donor-specific transplantation tolerance can be achieved and to explain how tolerance to self-antigens can be maintained in the periphery.

> Psoriasis is a chronic, inflammatory, hyperproliferative skin disease, in which autoimmunity plays a great role. Natural killer T cells (NK T cells), are suggested to be involved in the pathogenesis of different autoimmune diseases. To examine the involvement of CD3 + CD56 + NK T cells in the pathogenesis of psoriasis, we investigated the lymphocyte subpopulations obtained from blood samples of psoriatic patients before and after treatment, and of healthy controls, using two-colour flow cytometry. We found no significant differences between total T cells, total B cells, T helper cells, T cytotoxic cells and NK cells in patients with psoriasis before and after treatment and in controls. Increased percentage of memory T cells and decreased percentage of naive T cells was detected in psoriatic patients compared to controls, but these changes were not statistically significant. The CD3 + CD56 + cells of psoriatic patients were significantly decreased relative to controls. The percentage of CD3 + CD56 + cells increased after different antipsoriatic therapies, but remained significantly lower than those found in controls. CD3 + CD56 + cells of healthy controls were capable of rapid activation, while in psoriatic patients activated NK T cells were almost absent. The decrease in the number of CD3 + CD56 + cells may represent an intrinsic characteristic feature of patients with psoriasis, which is supported by the fact that after treatment NK T cells do not reach the values found in controls. In conclusion our results suggest that CD3 + CD56 + NK T cells could be actively involved in the development of Th1 mediated autoimmune diseases.

> Summary Background  Psoriasis is an immunologically mediated, probably autoimmune, disease in which T-helper type 1 cytokines play an important role. Established autoimmune diseases, with similar mechanistic characteristics to psoriasis, include multiple sclerosis, rheumatoid arthritis, type 1 diabetes mellitus and systemic lupus erythematosus. Natural killer (NK) and natural killer-T (NK-T) cells are considered key to the pathogenesis of these conditions, which are characterized by reduced numbers of NK cells in peripheral blood. NK and NK-T cells have been implicated in the pathogenesis of psoriasis and are present in plaques of psoriasis.

> We have compared the immune responses of mice immunized either with α-galactosylceramide (α-GalCer), capable of eliciting a CD1-metiated stimulation of Vα14 + NK T cells, or with lipoarabinomannan (LAM), a glycophospholipid derived from mycobacteria which is known to be presented by CD1b in humans. Within 24 h, α-GalCer induces a burst of IFN-γ secretion in vivo, and recall with antigen in vitro leads to the synthesis of IL-4 and IL-10 in addition to IFN-γ. Associated with this in vivo cytokine release is a polyclonal activation of splenic B and T cells. CD1-reactive NK T lymphocytes mediate these events, because none of them are observed in α-GalCer-immunized CD1 − / − mice. LAM immunization fails to promote similar early responses in vivo. Repeated exposure of mice to α-GalCer induces splenic T cells to secrete IL-4 and IL-10 but dramatically reduced levels of IFN-γ. Such a biasin the cytokine balance triggered by NK T cells stimulated with multiple doses of α-GalCer suggests that this compound might be useful in the induction of Th2 immune responses and the prevention of chronic inflammatory conditions mediated by Th1 cytokines.