Dataset Information

UV radiation recruits CD4+GATA3+ and CD8+GATA3+ T cells while altering the lipid microenvironment following inflammatory resolution in human skin in vivo.

ABSTRACT: Objectives:Solar ultraviolet radiation (UVR) has major adverse effects on human health. While the mechanisms responsible for induction of UVR-induced inflammation are well-documented, the mediation of its resolution and longer-term adaptive homeostasis is unknown. Therefore, we examined the skin immune and lipid profile over time following UVR inflammation. Methods:To investigate the self-resolving events of UVR inflammation in vivo, human skin was exposed to a single pro-inflammatory dose of UVR. Skin biopsies and suction blister fluid were taken at intervals up to 2 weeks post-UVR. The immune infiltrate was quantified by immunohistochemistry, and lipid mediators were profiled by liquid chromatography/mass spectrometry. Results:We identified that cellular resolution events including switching of macrophage phenotype apply to human sunburn. However, UVR-induced inflammation in humans involves a post-resolution phase that differs from other experimental models. We demonstrate that 2 weeks after the initiating UVR stimulus, there is considerable immune activity with CD8+GATA3+ T cells maintained in human skin. Our results challenge the dogma of CD4+FOXP3+ T cells being the main effector CD4+ T-cell population following UVR, with CD4+GATA3+ T cells the dominant phenotype. Furthermore, lipid mediators are elevated 14 days post-UVR, demonstrating the skin lipid microenvironment does not revert to the tissue setting occurring prior to UVR exposure. Conclusion:We have identified for the first time that CD4+GATA3+ and CD8+GATA3+ T-cell subpopulations are recruited to UVR-inflamed human skin, demonstrating discrepancies between the adaptive UVR response in mice and humans. Future strategies to abrogate UVR effects may target these T-cell subpopulations and also the persistent alteration of the lipid microenvironment post-UVR.

SUBMITTER: Hawkshaw NJ

PROVIDER: S-EPMC7114692 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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UV radiation recruits CD4<sup>+</sup>GATA3<sup>+</sup> and CD8<sup>+</sup>GATA3<sup>+</sup> T cells while altering the lipid microenvironment following inflammatory resolution in human skin <i>in vivo</i>.

Hawkshaw Nathan J NJ Pilkington Suzanne M SM Murphy Sharon A SA Al-Gazaq Norah N Farrar Mark D MD Watson Rachel Eb RE Nicolaou Anna A Rhodes Lesley E LE

Clinical & translational immunology 20200402 4

<h4>Objectives</h4>Solar ultraviolet radiation (UVR) has major adverse effects on human health. While the mechanisms responsible for induction of UVR-induced inflammation are well-documented, the mediation of its resolution and longer-term adaptive homeostasis is unknown. Therefore, we examined the skin immune and lipid profile over time following UVR inflammation.<h4>Methods</h4>To investigate the self-resolving events of UVR inflammation <i>in vivo</i>, human skin was exposed to a single pro-i ...[more]

PMID: 32257209

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Project description:Background and aimHuman papillomavirus (HPV) is an oncogenic agent that causes over 90% of cases of cervical cancer in the world. Currently available prophylactic vaccines are type specific and have less therapeutic efficiency. Therefore, we aimed to predict the potential species-specific and therapeutic epitopes from the protein sequences of HPV45 by using different immunoinformatics tools.MethodsInitially, we determined the antigenic potential of late (L1 and L2) and early (E1, E2, E4, E5, E6, and E7) proteins. Then, major histocompatibility complex class I-restricted CD8+ T-cell epitopes were selected based on their immunogenicity. In addition, epitope conservancy, population coverage (PC), and target receptor-binding affinity of the immunogenic epitopes were determined. Moreover, we predicted the possible CD8+, nested interferon gamma (IFN-γ)-producing CD4+, and linear B-cell epitopes. Further, antigenicity, allergenicity, immunogenicity, and system biology-based virtual pathway associated with cervical cancer were predicted to confirm the therapeutic efficiency of overlapped epitopes.ResultsTwenty-seven immunogenic epitopes were found to exhibit cross-protection (≥55%) against the 15 high-risk HPV strains (16, 18, 31, 33, 35, 39, 51, 52, 56, 58, 59, 68, 69, 73, and 82). The highest PC was observed in Europe (96.30%), North America (93.98%), West Indies (90.34%), North Africa (90.14%), and East Asia (89.47%). Binding affinities of 79 docked complexes observed as global energy ranged from -10.80 to -86.71 kcal/mol. In addition, CD8+ epitope-overlapped segments in CD4+ and B-cell epitopes demonstrated that immunogenicity and IFN-γ-producing efficiency ranged from 0.0483 to 0.5941 and 0.046 to 18, respectively. Further, time core simulation revealed the overlapped epitopes involved in pRb, p53, COX-2, NF-X1, and HPV45 infection signaling pathways.ConclusionEven though the results of this study need to be confirmed by further experimental peptide sensitization studies, the findings on immunogenic and IFN-γ-producing CD8+ and overlapped epitopes provide new insights into HPV vaccine development.

Project description:Background and purposeA lower proportion of CD8+ tumor infiltrating lymphocytes in mycosis fungoides (MF) patients is associated with worse survival. However, it is not known whether circulating CD4:CD8 ratio is a prognosticator of response to total skin electron beam therapy (TSEBT).Methods and materialsWe identified 126 MF patients treated with TSEBT from 2001 to 20014 at two high-volume academic centers. Circulating CD4:CD8 ratio was obtained within 1 week before TSEBT. TSEBT was delivered with 6-9mEV electrons with low (12 Gy) or conventional (≥12 Gy) doses. Treatment response was assessed with the modified Severity Weighted Assessment Tool (mSWAT). Post-treatment mSWAT decrease of ≥75% was classified as near complete response (CR) while mSWAT decrease of <75% was considered partial response (PR). Receiver operating characteristic analysis determined an optimal CD4:CD8 threshold value to predict TSEBT response in the derivation cohort and was applied to an external validation cohort.Results71.4% and 28.6% of patients achieved CR and PR after TSEBT. Higher CD4:CD8 ratio predicted poorer response: median CD4:CD8 in patients with PR vs. CR was 4.84 vs. 1.97 (p = 0.002). A threshold CD4:CD8 of 4.42 optimally discriminated in the discovery cohort patients with PR vs. XR (sensitivity 90%, specificity 59%, area under curve (AUC) = 0.71; p = 0.002). Within an independent test cohort (n = 32), 73.9% of patients with CD4:CD8 <4.42 achieved CR vs. 33.3% of those with CD4:CD8 ≥4.42 (p = 0.033). Among all patients with CD4:CD8 <4.42 (n = 73), 74% achieved CR with low-dose TSEBT vs. 93% with conventional dose TSEBT (p = 0.02). On multivariable logistic regression, CD4:CD8 remained a significant independent predictor of TSEBT response in all patients (OR = 0.107, 95% CI 0.395-0.290, p < 0.001).ConclusionPeripheral blood CD4:CD8 ratio was a significant independent predictor of TSEBT response of MF patients as validated in an independent cohort at separate academic center. The potential for CD4:CD8 ratio as a biomarker to inform radiation treatment dosing warrants further investigation.

Dataset Information

UV radiation recruits CD4+GATA3+ and CD8+GATA3+ T cells while altering the lipid microenvironment following inflammatory resolution in human skin in vivo.

Publications

UV radiation recruits CD4<sup>+</sup>GATA3<sup>+</sup> and CD8<sup>+</sup>GATA3<sup>+</sup> T cells while altering the lipid microenvironment following inflammatory resolution in human skin <i>in vivo</i>.

Similar Datasets

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