Expansion of Foxp3+ Regulatory T Cells in Mice Infected with the Filarial Parasite Brugia malayi

Abstract

Many helminths, including Brugia malayi, are able to establish long-lived infections in immunocompetent hosts. Growing evidence suggests that the immune system’s failure to eliminate parasites is at least partially due to the effects of regulatory T cells (Tregs). To test whether parasites may directly stimulate host regulatory activity, we infected mice with two key stages of B. malayi. Both mosquito-borne infective larvae and mature adults i.p. introduced were found to preferentially expand the proportion of CD25+Foxp3+ cells within the CD4+ T cell population. The induction of Foxp3 was accompanied by raised CD25, CD103, and CTLA-4 expression, and was shown to be an active process, which accompanied the introduction of live, but not dead parasites. CTLA-4 expression was also markedly higher on Foxp3− cells, suggesting anergized effector populations. Peritoneal lavage CD4+CD25+ cells from infected mice showed similar suppressive activity in vitro to normal splenic “natural” Tregs. Both B. malayi larvae and adults were also able to induce Foxp3 expression in adoptively transferred DO11.10 T cells, demonstrating that filarial infection can influence the development of T cells specific to a third party Ag. In addition, we showed that induction was intact in IL-4R-deficient animals, in the absence of a Th2 or alternatively activated macrophage response. We conclude that filarial infections significantly skew the balance of the host immune system toward Treg expansion and activation, in a manner dependent on live parasites but independent of a concomitant Th2 response.

CD4+Foxp3+ regulatory T cells mediate Toxoplasma gondii‐induced T‐cell suppression through an IL‐2‐related mechanism but independently of IL‐10

“…Since at the time point studied (7 dpi) a reduction of only 16.3% of Treg cells is observed, the activation and acquisition of a higher suppressive capacity of the remaining Treg cells could easily explain the ability of these cells to mediate immunosuppression. The activation of Treg cells described herein is consistent with data previously reported during other infectious diseases [46][47][48][49][50], and supports the idea that Treg-cell activation could be a natural response towards some pathogens. Whether Treg-cell activation depends on molecules derived from the parasite, on the proinflammatory environment, or both, remains to be established.…”

CCL17 Controls Mast Cells for the Defense against Filarial Larval Entry

“…In murine filariasis, regulatory T cells expand in numbers at the site of infection and are observed in the skin draining lymph nodes or coelomic cavities as early as day 7 p.i. (21,30). However, in CCL17…”

Fasciola hepatica tegumental antigens induce anergic‐like T cells via dendritic cells in a mannose receptor‐dependent manner

“…FoxP3 + Treg cells are the major cause of T-cell unresponsiveness in B. malayi infection [5] while infections with other helminths induce suppression or T-cell anergy [13,14,16]. Fasciola hepatica infection is typically associated with a polarized Th2/Treg immune response with a decrease in protective Th1 immune responses within hours post infection.…”

“…Treg cells supCorrespondence: Dr. Sandra M. O'Neill e-mail: sandra.oneill@dcu.ie press the immune response to helminth-driven Th1/Th2 immune pathology through the induction of IL-10 and TGF-β. Brugia malayi, infection induces a regulatory response with enhanced FoxP3 expression and increased cell surface expression of CTLA4, a negative regulator of T-cell function [5] while Schistosoma haematobium infection in humans has also been associated with FoxP3 + Treg cells with the highest percentage of this cell population observed in younger patients [6]. However, less is currently known about the regulatory response termed in vivo anergy or adaptive tolerance.…”