Suppression of ovine lymphocyte activation by Teladorsagia circumcincta larval excretory-secretory products

Tom N Mcneilly,Jeremy K Brown,Cassandra Longhi,Alasdair J Nisbet,Yvonne Bartley,Mara Rocchi,Jacqueline B Matthews,John F Huntley,David Frew,Jenni Mcintyre,Sean Wattegedera,Louise Mclean

doi:10.1186/1297-9716-44-70

Abstract

Teladorsagia circumcincta is an important pathogenic nematode of sheep. It has been demonstrated previously that stimulation of murine T lymphocytes with excretory-secretory (ES) products derived from fourth stage larvae of T. circumcincta (Tci-L4-ES) results in de novo expression of Foxp3, a transcription factor intimately involved in regulatory T cell function. In the current study, Foxp3+ T cell responses in the abomasum and the effects of Tci-L4-ES on ovine peripheral blood mononuclear cells (PBMC) following T. circumcincta infection were investigated. T. circumcincta infection resulted in a significant increase in numbers of abomasal Foxp3+ T cells, but not an increase in the proportion of T cells expressing Foxp3. Unlike in mice, Tci-L4-ES was incapable of inducing T cell Foxp3 expression but instead suppressed mitogen-induced and antigen-specific activation and proliferation of ovine PBMC in vitro. This effect was heat labile, suggesting that it is mediated by protein(s). Suppression was associated with up-regulation of interleukin-10 (IL-10) mRNA, and specific monoclonal antibody neutralisation of IL-10 resulted in a 50% reduction in suppression, indicating involvement of the IL-10 signaling pathway. Suppression was significantly reduced in PBMC isolated from T. circumcincta infected vs. helminth-naïve lambs, and this reduction in suppression was associated with an increase in Tci-L4-ES antigen-specific T cells within the PBMC. In conclusion, we have identified a mechanism by which T. circumcincta may modulate the host adaptive immune response, potentially assisting survival of the parasite within the host. However, the impact of Tci-L4-ES-mediated lymphocyte suppression during T. circumcincta infection remains to be determined.

Highlights

Teladorsagia circumcincta is a pathogenic nematode of small ruminants and represents a major constraint on farming
Primary infection with T. circumcincta results in recruitment of Foxp3+ T cells into the abomasal mucosa To determine whether Foxp3+ T cell levels increase locally during early infection, helminth-free lambs were challenged with a single infection of 50 000 T. circumcincta L3 and the numbers and location of Foxp3+ T cells within the abomasal mucosa determined at 0, 5 and 10 days postchallenge by IHC
As in the previous experiment, Tci-L4-ES was less able to suppress peripheral blood mononuclear cells (PBMC) from T. circumcincta infected lambs compared to PBMC obtained prior to infection (Figure 8A, P < 0.05). This reduction in suppression of PBMC was associated with a significant increase in proliferation of PBMC in response to Discussion Helminth infections are a major constraint to livestock production worldwide and represent a major challenge to continued food security

Summary

Introduction

Teladorsagia circumcincta is a pathogenic nematode of small ruminants and represents a major constraint on farming. In the absence of further parasite challenge, elements of the protective response which can, for example, result in the induction of inhibited L4, are comparatively short-lived, requiring continuous exposure to T. circumcincta to be maintained [6]. This relative delay in acquisition of immunity, as well as the somewhat incomplete nature of the protective response, suggests that, as with other nematode species [7,8], T. circumcincta may actively suppress host immune responses facilitating survival within the host. Cytokine mRNA profiles in abomasal lymph nodes derived from infected sheep suggest that, in common with other nematode infections [7], the effector response to T. circumcincta is largely Th2- type in nature, in concert with a regulatorytype response [13]

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