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γδ T cells located near the epithelial barrier are integral components of local inflammatory and innate immune responses. We have previously reported the presence of choroidal γδ T cells in a model of chronic degeneration of the retinal pigment epithelium (RPE). The goals of the current study were to further define the functions of choroidal γδ T cells and to explore the underlying mechanisms of their action. Our data demonstrate that choroidal γδ T cells are activated by RPE injury in response to NaIO3 treatment, and that they express genes that encode immunosuppressive cytokines, such as IL-4 and IL-10. γδ-T-cell-deficient mice developed profound RPE and retinal damage at doses that caused minimal effects in wild-type mice, and adoptive transfer of γδ T cells prevented sensitization. Intravitreal injection of IL-4 and IL-10 ameliorated RPE toxicity that was induced by NaIO3Ex vivo coculture of γδ T cells with RPE explants activated the production of anti-inflammatory cytokines via an aryl hydrocarbon receptor (AhR)-dependent mechanism. AhR deficiency abolished the protective effects of γδ T cells after adoptive transfer. Collectively, these findings define important roles for choroid γδ T cells in maintaining tissue homeostasis in the outer retina.-Zhao, Z., Liang, Y., Liu, Y., Xu, P., Flamme-Wiese, M. J., Sun, D., Sun, J., Mullins, R. F., Chen, Y., Cai, J. Choroidal γδ T cells in protection against retinal pigment epithelium and retinal injury.

The cAMP signalling pathway plays an essential role in immune functions. In the present study we examined the role of the cAMP/EPAC1 (exchange protein directly activated by cAMP) axis in regulatory T-cell (Treg)-mediated immunosuppression using genetic and pharmacological approaches. Genetic deletion of EPAC1 in Tregs and effector T-cells (Teffs) synergistically attenuated Treg-mediated suppression of Teffs. Mechanistically, EPAC1 inhibition enhanced activation of the transcription factor STAT3 (signal transducer and activator of transcription 3) and up-regulated SMAD7 expression while down-regulating expression of SMAD4. Consequently, CD4+ T-cells were desensitized to transforming growth factor (TGF) β1, a cytokine employed by Tregs to exert a broad inhibitory function within the immune system. Furthermore, deletion of EPAC1 led to production of significant levels of ovalbumin IgG antibodies in a low-dose, oral-tolerance mouse model. These in vivo observations are consistent with the finding that EPAC1 plays an important role in Treg-mediated suppression. More importantly, pharmacological inhibition of EPAC1 using an EPAC-specific inhibitor recapitulates the EPAC1 deletion phenotype both in vivo and in vitro. The results of the present study show that EPAC1 boosts Treg-mediated suppression, and identifies EPAC1 as a target with broad therapeutic potential because Tregs are involved in numerous pathologies, including autoimmunity, infections and a wide range of cancers.

Traditional tropospheric ozone (O3) climatology uses a simple average substantially smoothed stratification structure in individual O3 profiles, limiting our ability to properly describe and understand how O3 is vertically distributed at the interface between the mixing layer (ML) and free troposphere (FT). In this study, we collected 1897 ozonesonde profiles from two Chinese megacities (Beijing and Hong Kong) over the period 2000–2022 to investigate the climatological vertical heterogeneity of the lower-tropospheric O3 distribution with a mixing-layer-height-referenced (h -referenced) vertical coordinate system. The mixing-layer height (h) was first estimated following an integral method that integrates the information of temperature, humidity, and cloud. After that, a so-called h -referenced vertical distribution of O3 was determined by averaging all individual profiles expressed as a function of z/h rather than z (where z is altitude). We found that the vertical stratification of O3 is distributed heterogeneously in the lower troposphere, with stronger vertical gradients at the surface layer and ML–FT interface. There are low vertical autocorrelations of O3 between the ML and FT but high autocorrelations within each of the two atmospheric compartments. These results suggest that the ML–FT interface acts as a geophysical "barrier" separating air masses of distinct O3 loadings. This barrier effect varies with season and city, with an ML–FT detrainment barrier in summer (autumn) and an FT–ML entrainment barrier in other seasons in Beijing (Hong Kong). Based on a Student's t test, daily h -referenced O3 profiles were further classified into three typical patterns: MLO 3 -dominated, FTO 3 -dominated, and uniform distribution. Although the FTO 3 -dominated pattern occurs most frequently during the whole study period (69 % and 54 % of days in Beijing and Hong Kong, respectively), the MLO 3 -dominated pattern prevails in the photochemically active season, accounting for 47 % of summer days in Beijing and 54 % of autumn days in Hong Kong. These occurrences of the MLO 3 -dominated pattern are significantly more frequent than in previously reported results at northern mid-latitudes, indicating intensive photochemical MLO 3 production under the high-emission background of a Chinese megacity. From a FTO 3 -dominated to MLO 3 -dominated pattern, the O3 precursor CH2O (NO2) experiences a substantial increase (decrease) in Beijing but a slight change in Hong Kong. Vertically, the increment of CH2O is larger in the upper ML, and the decrement of NO2 is larger in the lower ML. Such vertical changes in O3 precursors push O3 production sensitivity away from the VOC-limited regime and facilitate high-efficiency production of O3 via photochemical reactions, particularly in the upper ML of Beijing. [ABSTRACT FROM AUTHOR]