Pronounced Phenotype in Activated Regulatory T Cells during a Chronic Helminth Infection

Abstract

Although several markers have been associated with the characterization of regulatory T cells (Tregs) and their function, no studies have investigated the dynamics of their phenotype during infection. Since the necessity of Tregs to control immunopathology has been demonstrated, we used the chronic helminth infection model Schistosoma mansoni to address the impact on the Treg gene repertoire. Before gene expression profiling, we first studied the localization and Ag-specific suppressive nature of classically defined Tregs during infection. The presence of Foxp3+ cells was predominantly found in the periphery of granulomas and isolated CD4+CD25hiFoxp3+ Tregs from infected mice and blocked IFN-γ and IL-10 cytokine secretion from infected CD4+CD25− effector T cells. Furthermore, the gene expression patterns of Tregs and effector T cells showed that 474 genes were significantly regulated during schistosomiasis. After k-means clustering, we identified genes exclusively regulated in all four populations, including Foxp3, CD103, GITR, OX40, and CTLA-4—classic Treg markers. During infection, however, several nonclassical genes were upregulated solely within the Treg population, such as Slpi, Gzmb, Mt1, Fabp5, Nfil3, Socs2, Gpr177, and Klrg1. Using RT-PCR, we confirmed aspects of the microarray data and also showed that the expression profile of Tregs from S. mansoni-infected mice is simultaneously unique and comparable with Tregs derived from other infections.

Of Mice and Microflora

“…Pinworms are relatively innocuous in most mice, with few reports of altered susceptibilities of GEM to parasite burden or infection with S. muris, the rat pinworm 41 ; however, they are a top differential diagnosis for rectal prolapse. Infection with helminths has experimentally been shown to alter immunophenotype, 64,47,112 and undetected natural infections could affect immunological studies. 52 Transmission is fecal-oral, and eggs are often aerosolized.…”

T Cell–Derived IL-4/IL-13 Protects Mice against Fatal Schistosoma mansoni Infection Independently of Basophils

“…Mice were analyzed 9-12 wk postinfection. Determination of egg burden in liver and small intestine was performed as described (42). Fecal egg burden was determined after fixation of stool samples with 4% formalin.…”

“…Fecal egg burden was determined after fixation of stool samples with 4% formalin. Samples were washed and passed through two layers of gaze, followed by centrifugation and microscopic examination of the sediment (42). …”

Mechanism of T cell exhaustion in a chronic environment

“…Under certain circumstances, conventional T cells have been known to differentiate into Tregs, called 'induced Tregs', resulting in the acquirement of Foxp3 expression and suppressive functionality (114,115). There are several studies showing enhancement in the frequency of natural and induced Tregs during helminthic infections (116,117) and bacterial infections such as Leshimania guyanensis (118), Listeria monocytogens (119), and Mycobacterium tuberculosis (120). Upon chronic viral infection, Tregs contribute to an increase in the viral load or the inhibition of antiviral T cell responses.…”