T lymphocytes are defective in cystine uptake and thus require exogenous thiols for activation and function. Here we show that monocyte-derived human dendritic cells (DCs) release cysteine in the extracellular space. Cysteine generation is increased by lipopolysaccharide and tumor necrosis factor alpha, and by contact with T cells specifically recognizing soluble or alloantigens. These stimuli also induce thioredoxin (TRX) accumulation in DCs. However, only the contact with antigen-specific T cells triggers TRX secretion by the antigen-presenting cells. Fewer extracellular thiols are recovered after DC-T cell interactions when cystine uptake or TRX activity are inhibited. In addition, glutamate (Glu) and anti-TRX-inactivating antibodies inhibit antigen-dependent T lymphocyte proliferation. These findings indicate that, during antigen presentation, DCs uptake cystine and release cysteine and TRX, thus providing a reducing microenvironment that facilitates immune response.

IntroductionInteraction among cells of the immune system is essential for the onset, progress, and end of immune-inflammatory reactions. Immune cells coordinate reciprocally their responses through signaling or release of appropriate soluble factors or both. A well-known example is given by dendritic cell (DC) priming of naive T cells, which depends on the formation of the immunologic synapse, a complex cluster of molecules organized at the contact area of cell conjugates. 1,2 Activation is not only one way, in that T lymphocytes also induce dramatic changes in DCs. This is well evident in mixed lymphocyte reactions, where alloreactive CD8 ϩ T cells trigger Ca 2ϩ rises in DCs, followed by release of interleukin 1-␤ (IL-1␤) at the immunologic synapse. 3,4 This polarized secretion of IL-1␤ may activate locally the interacting target cell, thus controlling immune response without spreading around the potentially dangerous cytokine. Similar results were observed for another member of the IL-1 family, 6 Both IL-1␤ and IL-18 are leaderless secretory proteins that do not follow the classical exocytotic route to get out of the cell. 7 Their secretion involves translocation of cytosolic molecules into secretory lysosomes. 4,6,8,9 These are calciumdependent secretory organelles, abundant in hemopoietic cells, that play the dual function of degradation and regulated secretion of proinflammatory factors. 10 Natural killer (NK) cells are lymphocytes active in innate responses against viruses, bacteria, and tumors, due to their potent cytotoxic activity and rapid production of cytokines. 11 Interestingly, NK cells have been shown to interact also with immature DCs (iDCs); this interaction seems crucial in the initiation/ amplification of the early phases of an immune response, before specific T cells are generated. [12][13][14][15][16][17] iDC-NK crosstalk results in activation of NK cells that, in turn, induces DC maturation or killing (or both). The differential fate of iDCs (death or maturation) may depend on dynamics of the iDCs and NK cells and their respective density. 16 However, the mechanisms underlying the reciprocal DC and NK cell activation are largely unknown. Various cytokines produced by DCs, including IL-12 and IL-18, upregulate NK cell cytotoxicity. 18,19 IL-18 is constitutively produced by iDCs, 5,20 whereas IL-12 is expressed after DC maturation. 21 This may suggest that IL-18 is the first dendrikine that triggers the activation of NK cells on NK/iDC interaction, whereas the involvement of IL-12 is a later event that occurs after the maturation of DCs induced by NK cells. Also, IL-15 may contribute to NK cell activation, but, like IL-12, its expression seems restricted to maturing DCs 22 ; furthermore, whether this cytokine is secreted by human DCs or just presented via DC membrane receptors is so far unclear. 23 The mechanisms underlying NK cell-mediated DC maturation are also uncertain; in humans, cell-cell interaction seems required [15][16] ; a role for tumor necrosis factor ␣ (TNF-␣) and interferon ␥ (...

Abnormal and excessive accumulation of the amyloid beta-peptide (A beta) in the brain is a major and common characteristic of all Alzheimer's disease (AD) forms irrespective of their genetic background. Insoluble aggregates of A beta are identified as amyloid plaques. These deposits are thought to form when the amount of A beta is increased in the brain parenchyma as a result of either overexpression or altered processing of the amyloid precursor protein (APP). Soluble A beta ending at carboxyl-terminal residue 40 (A beta 40) and, in lesser amount, the form ending at residue 42 (A beta 42), are normal products of the APP metabolism in cell cultures. Increased secretion of soluble A beta 42 has been observed in cells transfected with constructs modeling APP gene mutations of familial forms of AD (refs 4, 5). On the basis of these in vitro data it has been hypothesized that the presence of soluble A beta 42 plays a role in the formation of amyloid plaques. Subjects affected by Down's syndrome (DS) have an increased APP gene dosage and overexpress APP. Apparently because of this overexpression, they almost invariably develop amyloid deposits after the age of 30 years, although they are free of them at earlier ages. Moreover, it has been observed that A beta 42 precedes A beta 40 in the course of amyloid deposition in DS brain. Thus, DS subjects provide the opportunity to investigate in the human brain the metabolic conditions that precede the formation of the amyloid deposits. Here we report that soluble A beta 42 is present in the brains of DS-affected subjects aged from 21 gestational weeks to 61 years but it is undetectable in age-matched controls. It is argued that overexpression of APP leads specifically to A beta 42 increase and that the presence of the soluble A beta 42 is causally related to plaque formation in DS and, likely, in AD brains.

Uveal melanoma (UM), a rare cancer of the eye, is distinct from cutaneous melanoma by its etiology, the mutation frequency and profile, and its clinical behavior including resistance to targeted therapy and immune checkpoint blockers. Primary disease is efficiently controlled by surgery or radiation therapy, but about half of UMs develop distant metastasis mostly to the liver. Survival of patients with metastasis is below 1 year and has not improved in decades. Recent years have brought a deep understanding of UM biology characterized by initiating mutations in the G proteins GNAQ and GNA11. Cytogenetic alterations, in particular monosomy of chromosome 3 and amplification of the long arm of chromosome 8, and mutation of the BRCA1-associated protein 1, BAP1, a tumor suppressor gene, or the splicing factor SF3B1 determine UM metastasis. Cytogenetic and molecular profiling allow for a very precise prognostication that is still not matched by efficacious adjuvant therapies. G protein signaling has been shown to activate the YAP/TAZ pathway independent of HIPPO, and conventional signaling via the mitogen-activated kinase pathway probably also contributes to UM development and progression. Several lines of evidence indicate that inflammation and macrophages play a pro-tumor role in UM and in its hepatic metastases. UM cells benefit from the immune privilege in the eye and may adopt several mechanisms involved in this privilege for tumor escape that act even after leaving the niche. Here, we review the current knowledge of the biology of UM and discuss recent approaches to UM treatment.