T Regulatory Cell Subpopulations Associated with Recent Ultraviolet Radiation Exposure in a Skin Cancer Screening Cohort

Hesterberg, Rebecca S.; Amorrortu, Rossybelle P.; Zhao, Yayi; Hampras, Shalaka S.; Akuffo, Afua A.; Fenske, Neil A.; Cherpelis, Basil S.; Balliu, Juliana; Vijayan, Laxmi; Epling-Burnette, Pearlie K.; Rollison, Dana E.

doi:10.4049/jimmunol.1800940

Cited by 13 publications

(28 citation statements)

References 85 publications

(119 reference statements)

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“…It is thought that regulatory T cells (Tregs) are central for cutaneous immunosuppression following UVR exposure in mice . In addition, recent epidemiological evidence shows that the Treg subpopulation, CD45RA − /CD27 − , in the peripheral blood of humans, positively correlates with a proxy of UVR exposure . However, there is no in situ evidence that UVR leads to the accumulation of Tregs in human skin .…”

Section: Introductionmentioning

confidence: 99%

“…In addition, recent epidemiological evidence shows that the Treg subpopulation, CD45RA − /CD27 − , in the peripheral blood of humans, positively correlates with a proxy of UVR exposure . However, there is no in situ evidence that UVR leads to the accumulation of Tregs in human skin . Moreover, the potential role of efferocytosis, a vital process for initiating inflammatory resolution, remains unexplored in the human cutaneous UVR response.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…One possible explanation for these findings is the influence of UV radiation on the immune system. UV radiation exposure has been shown to correlate with subpopulations of circulating regulatory T cells (32), which could, in turn, influence beta HPV acquisition, replication, and/or persistence. Additional studies of immune function and beta HPV infection are needed, including studies conducted in immunocompetent individuals, in order to identify those at highest risk of beta HPV infection.…”

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confidence: 99%

An Emerging Issue in Oncogenic Virology: the Role of Beta Human Papillomavirus Types in the Development of Cutaneous Squamous Cell Carcinoma

Rollison

Viarisio

Amorrortu

et al. 2019

J Virol

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Evidence suggests that beta human papillomaviruses (HPVs), together with ultraviolet radiation, contribute to the development of cutaneous squamous cell carcinoma. Beta HPVs appear to be not the main drivers of carcinogenesis but rather facilitators of the accumulation of ultraviolet-induced DNA mutations. Beta HPVs are promoters of skin carcinogenesis, although they are dispensable for the maintenance of the malignant phenotype. Therefore, beta HPV represents a target for skin cancer prevention, especially in high-risk populations. KEYWORDS UV radiation, human papillomavirus, skin cancer T he human papillomavirus (HPV) family comprises approximately 200 types that are able to infect the mucosal and cutaneous epithelia (1). They are subdivided into genera and species in the HPV phylogenetic tree according to the DNA sequence of the late gene L1 (2). The genus Alphapapillomavirus includes the mucosal high-risk (HR) HPV types that have been clearly associated with the development of cervical and anal cancers and a subset of other genital tract cancers, such as vulvar, vaginal, and penile carcinomas, as well as a subset of head and neck cancers (3). More than 40 years of research have elucidated many of the HR HPV mechanisms involved in cancer development. The products of two early genes, E6 and E7, are major oncoproteins able to deregulate many key cellular events and greatly facilitate the malignant transformation of the infected cells. Classic examples of processes targeted by HR HPV E6 and/or E7 oncoproteins are the cell cycle, DNA repair, apoptosis, senescence, and the immune response (4). In the context of the viral life cycle, these activities of E6 and E7 are essential to guarantee viral DNA replication and progeny production. As a side effect, they facilitate the accumulation of chromosomal abnormalities, leading to cancer development. Despite the accumulation of this DNA damage, constant expression of the viral oncogenes is required for the maintenance of the transformed phenotype. Indeed, experiments in in vitro models have shown that silencing of E6 and E7 expression in cervical cancer-derived cell lines, such as CaSki or HeLa, severely affects cell viability (5-8). Because of the biological properties of the HR HPV E6 and E7 in directly targeting several cellular proteins/pathways, HPV-positive cancer cells do not usually accumulate many mutations compared with cancers associated with other environmental factors. For instance, HPV-negative oropharyngeal cancers have more DNA mutations, which are often linked to tobacco use and/or alcohol consumption, compared with HPV-positive oropharyngeal cancers (9).Similar to the HR HPV types, cutaneous beta HPV types have also been implicated in carcinogenesis, although the model of carcinogenesis is quite different. Epidemiological and biological studies support the model of synergistic cooperation between Citation Rollison DE, Viarisio D, Amorrortu RP, Gheit T, Tommasino M. 2019. An emerging issue in oncogenic virology: the role of beta human papillomavirus types...

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“…Some limitations of the study are noted. A number of host and environmental factors, including age, medical conditions and ultraviolet radiation, have been associated with circulating Treg cells . While all analyses were adjusted for age and sex, it is possible that circulating activated effector Treg cells are a surrogate marker for an underlying condition or exposures that impact γ HPV infection.…”

Section: Discussionmentioning

confidence: 99%

“…Viably frozen PBMCs were used to assess proportions of circulating Treg cells from peripheral blood samples using antibodies shown in Figure S1 (BD Biosciences; Table S1, see Supporting Information) and staining methods described previously . Proportions of the following circulating T cells were derived as follows: (i) CD4 + and CD8 + T cells (CD3 + CD4 + and CD3 + CD4 – among total T cells); (ii) total Treg cells and non‐Treg CD4 + T‐cells (CD3 + CD4 + CD25 + FOXP3 + and CD3 + CD4 + CD25 – FOXP3 – , respectively, among CD3 + CD4 + T cells); (iii) Treg cells with naïve and post‐activation markers including CD45RA + /CD27 + naïve, CD45RA – /CD27 + long‐term memory, CD45RA + /CD27 – exhausted and CD45RA – /CD27 – activated ‘effector’ Treg cells, as defined previously; (iv) ‘skin‐homing’ cutaneous lymphocyte antigen (CLA) + Treg cells (% of CLA + cells among Treg cells) and (iv) ‘skin‐homing’ CCR4 high Treg cells (% of CCR4 + cells among Treg cells) (Fig. S1; see Supporting Information).…”

Section: Methodsmentioning

confidence: 99%

Cross‐sectional associations between cutaneous viral infections and regulatory T lymphocytes in circulation

Hampras¹,

Tommasino

Zhao³

et al. 2019

Br J Dermatol

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Summary Background Cutaneous viral infections and immune suppression are risk factors for some forms of nonmelanoma skin cancer; however, their interrelationship is poorly understood. Objectives To examine cross‐sectional associations between cutaneous viral infections and circulating forkhead‐box P3 (FOXP3)‐expressing T‐regulatory (Treg) cells, suppressive cells that dampen effective antitumour immunity. Materials and methods Blood, eyebrow hair (EBH) and skin swab (SSW) samples were collected from 352 patients 60 years and older undergoing skin screening, without prevalent skin cancer, while participating in an ongoing prospective cohort study of cutaneous viral infections and skin cancer. DNA corresponding to 98 cutaneous human papillomavirus (HPV) types and five human polyomaviruses (HPyV) was assessed in EBH and SSW. Distinct classes of circulating Treg‐cell subpopulations were defined by flow cytometry including cutaneous lymphocyte antigen (CLA) and CCR4high Treg cells, both previously associated with cutaneous diseases. Age‐ and sex‐adjusted associations between circulating T‐cell populations and infection were estimated using logistic regression. Results Total Treg‐cell proportion in peripheral blood was not associated with β HPV or HPyV infection. However, the proportion of circulating CLA+ Treg cells was inversely associated with γ HPV EBH infection [odds ratio (OR) 0·54, 95% confidence interval (CI) 0·35–0·84]. Interestingly, circulating Treg cells expressing markers indicative of antigen activation (CD27–CD45RA–FOXP3+CD4+) were also inversely associated with γ HPV infection in SSW (OR 0·55, 95% CI 0·30–0·99) and EBH (OR 0·56, 95% CI 0·36–0·86). Conclusions Inverse associations between circulating Treg cells and γ HPV infection suggest that localized viral infection may promote immunosuppressive cell migration into skin.

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T Regulatory Cell Subpopulations Associated with Recent Ultraviolet Radiation Exposure in a Skin Cancer Screening Cohort

Cited by 13 publications

References 85 publications

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

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

An Emerging Issue in Oncogenic Virology: the Role of Beta Human Papillomavirus Types in the Development of Cutaneous Squamous Cell Carcinoma

Cross‐sectional associations between cutaneous viral infections and regulatory T lymphocytes in circulation

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T Regulatory Cell Subpopulations Associated with Recent Ultraviolet Radiation Exposure in a Skin Cancer Screening Cohort

Cited by 13 publications

References 85 publications

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

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

An Emerging Issue in Oncogenic Virology: the Role of Beta Human Papillomavirus Types in the Development of Cutaneous Squamous Cell Carcinoma

Cross‐sectional associations between cutaneous viral infections and regulatory T lymphocytes in circulation

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Product

Resources

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

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