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18). In addition, TCR engagecharacteristic of 'memory' T lymphocytes. 1-5 A high percentment results in Zap70 activation after its binding to the tyrosylage of the malignant cells constitutively express BE2, a late phosphorylated immunoreceptor tyrosine-based activation activation marker of 78 kDa, that appears on cloned normal motifs (ITAMs) of the chains and the CD3 complex 23,24 (for T cells only after stimulation with specific antigen, and on review see Ref. 25) and in rapid tyrosine phosphorylation and freshly isolated normal T cells in response to mitogens, 6,7 sugactivation of Syk. 26 The signaling initiated by TCR activation gesting that CTCL cells have been activated by their surroundis transmitted from the cell membrane through the cytoplasm ing dermal environment. Since CTCL lymphocytes can proto the nucleus and induces quiescent T cells to undergo cell liferate in the cutaneous compartment but are extremely division and maturation, processes critical for clonal expandifficult to cultivate in vitro, their neoplastic growth appears sion and initiation of the immune responses. to reflect in vivo stimulation, possibly through their TCR, orWe selected for investigation several immediate key reacantigen-independent pathways or cytokines. IL-7 might be one tions essential for T cell receptor-mediated signal transducof the required growth factors for CTCL cells in the skin since tion, proliferation and effector functions. Our results, based transgenic mice constitutively producing IL-7 developed on analysis of a limited sample of CTCL cells (from four extensive dermal infiltration followed by dermotropic lympatients), show nevertheless, common characteristics, ie phoma. 8,9 However, although IL-7 is produced by keradeficiencies in critical immediate functions associated with tinocytes, it is a weak in vitro CTCL mitogen, 10 and purified TCR activation. These include molecules participating in populations of CTCL cells were sustained in culture for only events proximal and distal to the TCR such as: (1) reduced a short period (such as a week) by mixtures of cytokines that levels of basal and stimulated tyrosyl-phosphorylated proteins include IL-7 and IL-2. 11,12 belonging to a wide range of signaling molecules; The preferential expression of CD45RO and the clonal TCR (2) suppressed specific activity of membrane-bound Csk and rearrangement suggest that CTCL clones have encountered a Lck; (3) failure to activate membrane-bound PTPase; (4) failure to activate Zap70 and to induce its association with the TCR chain; and (5) reduced expression and activity of Syk. LimitedCorrespondence: R Halaban, Department of Dermatology, Yale Unicomparative analysis with the CD4 + /CD45RO + subpopulation

Monoclonal antibodies to human T cells permit the characterization of the surface phenotype of cutaneous T cell lymphoma (CTCL). The majority of CTCL cells are reactive with OKT1 and OKT3 monoclonals, which identify peripheral T cells and mature thymocytes. The neoplastic cells also react with OKT4, which recognizes the inducer T cell subset; they are, however, unreactive with OKT5 monoclonal, which identifies cytotoxic/suppressor T cell subsets. These data are in agreement with previous functional studies demonstrating that CTCL is a neoplasm of inducer (helper) T cells.

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A series of monoclonal antibodies directed against T cell differentiation antigens was used to identify circulating T cells in normal human neonates. Twenty-five cord blood samples, taken after cesarean or vaginal delivery, and 16 venous blood samples from normal adult controls were examined using monoclonal antibodies in an indirect immunofluorescence technique. The percentage of circulating OKT3 positive (pan-T cell) cells was significantly lower in the neonatal blood (52.8%) compared with the adult controls (74.9%) (P less than .001). Of the cord mononuclear cells, 58% showed reactivity with OKT10 (common thymocyte antigen) compared with only 7% in adult controls (P less than .001). The helper:suppressor T cell ratio was lower in cord blood (1:2) as compared with 1:3 for adult blood (P less than .005) as observed in these studies. These figures reflect the presence of a significant population (25%) of immature T cells in cord blood that expresses simultaneously both helper (OKT4) and suppressor (OKT8) phenotypes. Twenty-four percent of the T cells in cord blood also expressed OKT6 antigen (cortical thymocyte), a feature not found in adult blood. Double-labeling studies characterized a previously undescribed blood T cell phenotype, which was simultaneously OKT6 and OKT3 (pan-T cell) positive; of the cells reactive with OKT3, 43% also were positive with OKT6. This study reveals the presence of immature populations of T cells in normal human neonatal blood exhibiting phenotypes characteristic of normal developing thymocytes and a previously undescribed cell phenotype.

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The vascular and inflammatory response in Rosacea is exacerbated by exposure to UV radiation. In this study we hypothesized that the excess LL37 known to be present in Rosacea skin may be responsible for this increased sensitivity to UV. To test this, human keratinocytes (NHEK) expressing LL37 were exposed to UVB (25 mJ/cm 2 ), then extracts from these cells, or control cell extracts of non-irradiated NHEK, were added to dermal microvascular endothelial cells (HDMECs). UV-damaged NHEK, but not controls, activated endothelial cells as seen by increased CXCL10 (4.03 fold, p¼0.03) and CX3CL1 (13.6 fold, p<0.0001). This activation of endothelial cells was due to release of dsRNA from UV exposed NHEK since RNAase treatment of the NHEK extract inhibited the response of HDMECs. HDMECs treated with a synthetic dsRNA (snoU1 RNA) required LL37 for activation, a process we refer to as innate immune vetting. To further understand the significance of this vetting phenomenon in rosacea, RNA-sequencing was performed on HDMECs. 117 unique genes were upregulated only by the combination of dsRNA and LL37. As expected, a GO pathway for type I interferon signaling was seen, but HDMECs also showed gene signatures for cell-cell adhesion. q-RT-PCR then validated induction of ICAM1 (10.74 fold, p¼ 0.0406) and VCAM1 (13.9 fold, p¼ 0.0051) by LL37-dsRNA. The role of dsRNA was confirmed by knock down of TLR3 (VCAM1 inhibited 6.02 fold, p¼ 0.0017). Consistent with induction of VCAM1 by RNA-LL37, we also observed that dsRNA-LL37 increased VCAM protein expression, enhanced monocyte adhesion to HDMECs (76.51 fold, p<0.0001), and increased leukocyte transmigration (5.11 fold, p<0.0001) across HDMECs. In mice, only combined injection of U1 and LL37 enhanced VCAM1 expression. These findings prompted examination of human Rosacea biopsies that also showed VCAM1 to be highly expressed in rosacea skin, a finding not previously known in this disorder. Overall, our results suggest LL37 acts as an innate immune vetting molecule in rosacea that enhances activation of endothelial cells after UV exposure. Premature skin aging evidenced by a rough skin texture and wrinkles is known to be driven by external factors, mainly by sunlight and in particular UV radiation including UVB (280-320 nm) and UVA (320-400 nm). However, recent advance highlighted the role of visible light and especially the blue light part (400-500nm) in skin aging. As the blue light is the highest energetic wavelength of the visible light, it penetrates deeper into the skin and damages the skin by inducing oxidative stress and production of proteases which degrade the extracellular matrix of the dermis. We first investigated the negative effects of the blue light in human dermis through the evaluation of MMP1 by immunostaining and image analysis on living skin biopsies exposed to blue light irradiation (peak at 250 nm-85 J/cm 2 ). We further evaluated the blue light preventive effect of a botanical extract selected for its ability to prevent UVB induced oxidative damages by promoting DNA ...