Accumulation and activation of epidermal γδ T cells in a mouse model of chronic dermatitis is not required for the inflammatory phenotype

Abstract

Chronic skin inflammation resulting from a defective epidermal barrier is a hallmark of atopic dermatitis (AD). We previously demonstrated that mice lacking FGF receptors 1 and 2 in keratinocytes (K5-R1/R2 mice) develop an AD-like chronic dermatitis as a result of an impaired epidermal barrier. Here, we show that γδ T cells, which rapidly respond to various insults, accumulate in the epidermis of K5-R1/R2 mice before the development of histological abnormalities. Their number and activation further increase as the phenotype progresses, most likely as a consequence of increased expression of Il-2 and Il-7 and the stress-induced proteins Rae-1, H60c, Mult1, PlexinB2, and Skint1. To determine the role of γδ T cells in the skin phenotype, we generated quadruple mutant K5-R1/-R2 mice lacking γδ T cells. Surprisingly, loss of γδ T cells did not or only marginally affect keratinocyte proliferation, epidermal thickness, epidermal barrier function, and accumulation and activation of different immune cells in the skin of K5-R1/R2 mice, possibly due to partial compensation by αβ T cells. These results demonstrate that γδ T cells do not contribute to the development or maintenance of chronic inflammation in response to a defect in the epidermal barrier. Keywords: Atopic dermatitis r Barrier function r Dendritic epidermal T cells r Inflammation r T cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe skin is the first line of defense against the environment and protects against excessive water loss and penetration of pathogens, allergens, or irritants. The cornified envelope and the associated lipid bilayer as well as tight junctions are the major components of the epidermal barrier [1]. Their importance is reflected by the findings that genetic or epigenetic alterations in genes encoding protein components of these structures are linked to the development of chronic inflammatory skin diseases, such as atopic dermatitis (AD) [2].Correspondence: Dr. Sabine Werner e-mail: sabine.werner@biol.ethz.ch FGF signaling in keratinocytes plays an important role in the control of epidermal barrier function. Thus, mice lacking FGF receptors (FGFR) 1 and 2 in keratinocytes (K5-R1/R2 mice) show severe transepidermal water loss (TEWL) due to downregulation of tight junction components. As a consequence, they develop chronic dermatitis with strong similarities to AD [3,4]. Consistent with the mouse data, reduced expression of FGFR1 and FGFR2 was detected in the skin of AD patients [5], and single nucleotide polymorphisms in the FGFR1 and FGFR2 genes were linked to atopy [6].Besides the mechanical barriers, various immune cells, including Langerhans cells [7], conventional αβ T cells, and unconventional γδ T cells [8,9] contribute to skin homeostasis. γδ T cells represent only a small percentage of all T cells in the epidermis (1-10%) and dermis (2-9%) of human skin [10,11]. However,www.eji-journal.eu 2518 Jitka Sulcova et al. Eur. J. Immunol. 2015. 45: 2517-25...

Mouse genetics identifies unique and overlapping functions of fibroblast growth factor receptors in keratinocytes

“…FGFR3 in keratinocytes is even dispensable for wound healing, in spite of its up-regulation in wounded mouse skin. 6,7 These findings suggest that fibroblasts are activated as a consequence of the epidermal abnormalities. [10][11][12][13] However, our findings are consistent with data from human keratinocytes demonstrating that knock-down of FGFR3 does not affect normal keratinocyte growth in vitro, 25 even though this receptor is strongly expressed in the human epidermis.…”

“…4,6,7 This finding demonstrates that FGFR1 signalling is unmasked in the absence of FGFR2, probably through FGF10/FGF22 signalling to the b splice variant of FGFR1. 4,6,7 This finding demonstrates that FGFR1 signalling is unmasked in the absence of FGFR2, probably through FGF10/FGF22 signalling to the b splice variant of FGFR1.…”

“…4,6,7 This finding demonstrates that FGFR1 signalling is unmasked in the absence of FGFR2, probably through FGF10/FGF22 signalling to the b splice variant of FGFR1. 4,[6][7][8] It results from a defect in the epidermal barrier that is caused at least in part by decreased expression of major tight junction components that are under direct control of FGFR signalling in keratinocytes, 4,[6][7][8] We is also expressed in the murine epidermis, 9 we speculated that loss of this receptor in K5-R1/R2 mice would aggravate the phenotype. 4,[6][7][8] It results from a defect in the epidermal barrier that is caused at least in part by decreased expression of major tight junction components that are under direct control of FGFR signalling in keratinocytes, 4,[6][7][8] We is also expressed in the murine epidermis, 9 we speculated that loss of this receptor in K5-R1/R2 mice would aggravate the phenotype.…”

“…4,[6][7][8]14 To generate mice lacking a functional FGFR3 protein in keratinocytes, we mated mice with floxed FGFR3 alleles 15 with K5-Cre mice. 4,[6][7][8]14 To generate mice lacking a functional FGFR3 protein in keratinocytes, we mated mice with floxed FGFR3 alleles 15 with K5-Cre mice.…”

“…6 Twenty-five consecutive measurements were taken from four different places on the back on different days. TEWL was determined using a Tewameter (Courage and Khazaka Electronic GmbH) as described previously.…”