Editors' Picks

        Side effects on the rise

        Although treatment with the anti–programmed death 1 (PD-1) receptor antibody nivolumab plus ipilimumab has resulted in increased survival in melanoma patients, a significant increase in eruption of psoriasiform dermatitis (PsD) has been observed in these patients. Imai and colleagues examined the effects of PD-1 in an imiquimod-induced mouse psoriasis model. Genetic deficiency of PD-1 enhanced the psoriasis-like inflammatory phenotype, including enhanced dermal inflammation, epidermal acanthosis, and neutrophilic abscess formation following imiquimod treatment. These animals also exhibited enhanced cutaneous expression of the inflammatory cytokines IL-17A and IL-22, which in turn recruit more neutrophils to the skin. These studies suggested that PD-1, which is expressed on γδ-low T cells, suppresses the production of proinflammatory cytokines, such as IL-17A, a cytokine that is central to psoriasiform inflammation. Thus, PD-1 may play a regulatory role in PsD. Our understanding of this contribution is critical because increasing numbers of melanoma patients will be treated with these checkpoint inhibitors. (J Immunol, published online 5 June 2015; doi:10.4049/jimmunol.1500448) Selected by B. Gilchrest

        Skin-homing ambassadors

        Memory T cells are directed to the skin by factors present in the distinct tissue environments. The chemokine receptor CCR8, which is highly expressed by memory T cells in the skin, is induced during naive T-cell activation by soluble epidermal tissue–derived factors. McCully and colleagues recently examined the mechanism behind this process, which is essential for the maintenance of immune surveillance and barrier integrity. The active vitamin D3 metabolite 1α,25-dihydroxyvitamin D3, which has been implicated in T-cell homing previously, and prostaglandin E2 synergistically induced expression of CCR8 on memory T cells. This induction required cAMP and exposure to the inducers during or before T-cell activation. Although the factors that induce CCR appear to differ between mice and humans, conservation of the regulation of skin homing by CCR8 expression suggests that further studies of this mechanism are suitable in mouse models of skin infections. (J Immunol 195:96–104, 2015) Selected by S. Hwang

        Surprisingly high

        Based on the notion that tumor evolution involves accumulation of driver mutations in cancer genes in normal cells prior to transformation, Martincorena and colleagues studied the mutational processes and clonal expansion of somatic mutations by ultradeep sequencing of 74 cancer genes in 234 normal epidermal biopsy samples from sun-exposed eyelids of four individuals. The frequency of driver mutations in these samples was surprisingly high. Although the pattern of mutations was as expected for UV light exposure, the mutations and selective forces acting in normal skin closely matched that of cutaneous squamous-cell carcinoma. Interestingly, the mutation burden of a normal cell was found to be 2–6 mutations per Mb per cell, and positively selected mutations were present in 18–32% of the skin cells that remained functionally and physiologically normal, highlighting the exceptional tumor suppressive capabilities of the skin. (Science 348:880–86, 2015) Selected by S. Getsios and S. Yuspa

        Full of fibrogenic potential

        Fibroblasts comprise a heterogeneous cell population that displays functional diversity with respect to wound repair. Rinkevich and colleagues identified a minimum of two functionally distinct fibroblast lineages in mouse dorsal skin. The Engrailed-1 lineage was primarily responsible for connective tissue deposition during embryonic development, cutaneous wound healing, radiation fibrosis, and cancer stroma formation. Lineage-specific cell ablation resulted in diminished connective tissue deposition in wounds and reduced melanoma growth. The fibrogenic properties of these cells were cell intrinsic because the site-specific differences of dermal architecture between oral and cutaneous dermis remained unaffected by transfer to a new tissue location. Furthermore, the investigators isolated these cells based on the expression of CD26/dipeptidyl peptidase-4, and small-molecule inhibition of the enzymatic activity of this marker diminished cutaneous scarring, suggesting that similar clinical manipulation may provide useful therapeutic strategies for fibrotic disease, wound healing, and cancer progression. (Science 348:aaa2151, 2015) Selected by L. Garza

        With just a drop of blood

        The compendium of viruses that infect humans (termed the “human virome”) profoundly affects human health, in part via alterations in host immunity that leave an indelible footprint on the immune system. Currently, viral infections are most commonly detected using serological or nucleic acid–based methods, although these assays typically only detect current infections with sufficient titers. Xu and colleagues recently reported VirScan, a high-throughput method for the comprehensive analysis of antiviral antibodies in human sera. This method, which employs DNA microarray synthesis and bacteriophage display in conjunction with immunoprecipitation and high-throughput DNA sequencing, was used to analyze sera from 569 human donors and a total of 108 antibody–peptide interactions. This sensitive and specific technique is also fairly cost-efficient and can be performed with only 1 μl of blood. Furthermore, B-cell responses were found to target highly similar viral epitopes across individuals, suggesting that these antibodies recognize substantially conserved public epitopes for each virus. Thus, VirScan will undoubtedly provide a powerful tool for exploration of the effects of host–virome interactions on human health and disease. (Science 348:aaa0698, 2015) Selected by J. Uitto