Nowak, K; Linzner, D; Thrasher, AJ; Lambert, PF; Di, WL; Burns, SO; (2017) Absence of γ-chain in keratinocytes alters chemokine secretion resulting in reduced immune cell recruitment. Journal of Investigative Dermatology , 137 (10) pp. 2120-2130. 10.1016/j.jid.2017.05.024.

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Abstract

Loss of function mutations in the common gamma (γc) chain cytokine receptor subunit give rise to severe combined immunodeficiency (SCID) characterised by lack of T and natural killer cells and infant death from infection. Haematopoietic stem cell transplantation or gene therapy offer cure but despite successful replacement of lymphoid immune lineages a long-term risk of severe cutaneous human papilloma virus (HPV) infections persists, possibly related to persistent γc-deficiency in other cell types. Here we demonstrate that keratinocytes, the only cell type directly infected by HPV, express functional γc and its co-receptors. Following stimulation with the γc-ligand IL-15, γc-deficient keratinocytes demonstrate significantly impaired secretion of specific chemokines including CXCL1, CXCL8 and CCL20 resulting in reduced chemotaxis of dendritic cells and CD4+ T-cells. Furthermore, γc-deficient keratinocytes also exhibit defective induction of T-cell chemotaxis in a model of stable HPV18 infection. These findings suggest that persistent γc-deficiency in keratinocytes alters immune cell recruitment to the skin which may contribute to the development and persistence of warts in this condition and would require novel treatment approaches.

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