Chronic Infection Drives Expression of the Inhibitory Receptor CD200R, and Its Ligand CD200, by Mouse and Human CD4 T Cells

Stefano Caserta,Amy Sawtell,Andrew S Macdonald,Rebecca Drummond,Rose Zamoyska,Francisca Mutapi,Norman Nausch,Tom Barr,Mauricio Martins Rodrigues

doi:10.1371/journal.pone.0035466

Abstract

Certain parasites have evolved to evade the immune response and establish chronic infections that may persist for many years. T cell responses in these conditions become muted despite ongoing infection. Upregulation of surface receptors with inhibitory properties provides an immune cell-intrinsic mechanism that, under conditions of chronic infection, regulates immune responses and limits cellular activation and associated pathology. The negative regulator, CD200 receptor, and its ligand, CD200, have been shown to regulate macrophage activation and reduce pathology following infection. We show that CD4 T cells also increase expression of inhibitory CD200 receptors (CD200R) in response to chronic infection. CD200R was upregulated on murine effector T cells in response to infection with bacterial, Salmonella enterica, or helminth, Schistosoma mansoni, pathogens that respectively drive predominant Th1- or Th2-responses. In vitro chronic and prolonged stimuli were required for the sustained upregulation of CD200R, and its expression coincided with loss of multifunctional potential in T effector cells during infection. Importantly, we show an association between IL-4 production and CD200R expression on T effector cells from humans infected with Schistosoma haematobium that correlated effectively with egg burden and, thus infection intensity. Our results indicate a role of CD200R:CD200 in T cell responses to helminths which has diagnostic and prognostic relevance as a marker of infection for chronic schistosomiasis in mouse and man.

Highlights

Among parasitic diseases, schistosomiasis is a major cause of morbidity in the developing world with high prevalence and serious disease-associated disability and socio-economic impact [1,2]
We investigated CD200 receptors (CD200R) expression in PBMC from individuals endemically exposed to Schistosoma haematobium, the cause of urinary schistosomiasis
We showed that the inhibitory receptor:ligand pair of molecules, CD200R:CD200, was upregulated on CD4 T cells during persistent infection

Summary

Introduction

Schistosomiasis is a major cause of morbidity in the developing world with high prevalence and serious disease-associated disability and socio-economic impact [1,2]. Children generally lack adaptive immunity to schistosomes and are more likely to accumulate substantial worm burden resulting in diminished physical fitness and impaired development [4]. How effective anti-helminth immunity is developed and maintained is still unknown and early prognostic tools to distinguish individuals more likely to progress into severe disease are needed. Re-exposure to helminth-derived antigens (Ag) induces T cell anergy [6], potentially undermining pathogen elimination, yet it remains undetermined whether anergy is a risk factor for disease severity in schistosomiasis. Immune responses must be initiated and terminated appropriately to maintain peripheral tolerance and immune homeostasis. In this context, T cell suppression/anergy might be beneficial to limit immune-mediated damage and fibrosis in selftissues in severe schistosomiasis

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Results

Conclusion