Both tumour cells and infiltrating T-cells in equine sarcoids express FOXP3 associated with an immune-supressed cytokine microenvironment

A Douglas Wilson,Chelsea Hicks

doi:10.1186/s13567-016-0339-8

Abstract

Bovine papillomavirus (BPV) infections of equine species have a central role in the aetiology of equine sarcoids; a common benign skin tumour of horses, zebras and donkeys. Within the lesions, all of the early papillomavirus genes are expressed and promote the excessive replication of fibroblasts which characterise these tumours. Equine sarcoids differ from BPV induced fibro-papillomas of cattle (the natural host of BPV), in that they do not produce high amounts of virus particles, do not usually regress spontaneously and do not sero-convert to BPV; features which suggest that affected horses lack an effective anti-viral immune response to BPV. Equine sarcoids contain large numbers of CD4+ CD8+ dual positive T-cells which uniformly express FOXP3, the key transcription factor of regulatory T-cells, and FOXP3 is also expressed within the BPV infected fibroblasts. Compared to healthy skin, sarcoids showed increased mRNA transcription for FOXP3 and the regulatory cytokine TGFβ. Transcription of IL17, which has been shown to have a regulatory function in human papillomavirus-associated tumours, was also elevated in equine sarcoids compared to spleen. In contrast, the levels of mRNA transcripts for effector T cell cytokines IL2, IL4 and interferon-gamma (IFNγ) were not elevated in sarcoids compared to healthy skin or spleen. Similarly neither interferon-alpha (IFNα), interferon-beta (IFNβ) nor IL12 family members were elevated in sarcoids compared to normal skin. We suggest that the regulatory cytokine micro-environment within sarcoids enables the persistence of the lesions by preventing an effective anti-viral immune response.Electronic supplementary materialThe online version of this article (doi:10.1186/s13567-016-0339-8) contains supplementary material, which is available to authorized users.

Highlights

Papillomaviruses are among the most widespread of animal viruses, with many hosts harbouring multiple virus types
Individual T-cells were distributed throughout the tumour, infiltrating between the fibroblasts (Figure 1A), at higher power the T-cells had an activated blast morphology with the presence of distinct membrane staining surrounding an area of cytoplasm with a central nucleus
The epidemiology of equine sarcoids indicates that Bovine papillomavirus (BPV) is transmissible among animals following prolonged close contact [40, 41], implying that it can complete its replication cycle and produce infectious virus within equine hosts

Summary

Introduction

Papillomaviruses are among the most widespread of animal viruses, with many hosts harbouring multiple virus types. Phylogenetic studies show that the papillomaviruses within a specific host often have a degree of similarity, indicating that host and virus have coevolved over a prolonged period of time during which new variants slowly emerged as mutations accumulated within the virus genome [1]. Phylogenetic studies have revealed cases where closely related papillomavirus are found in separate host species indicating that transfer of papillomavirus infections across species does occur and may lead to the [more rapid] emergence of new papillomavirus types [1]. Bovine papillomavirus 1 and 2 (BPV1, BPV2) provide examples of cross species infection, in that both virus types cause fibropapilloma lesions in cattle (Bos taurus) and are associated with the occurrence of sarcoids in domestic horses (Equus caballus), donkeys (Equus asinus) and zebras (Equus zebra) [2,3,4]. In equine spp. sarcoids is a collective term for a group of non-resolving pathological skin lesions, characterised by proliferation of fibroblasts along with the presence of DNA from BPV1 or BPV2: together these lesions comprise the commonest skin tumours in equines [5]

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