Regulation of primary Strongyloides ratti infections in mice: a role for interleukin‐5

To escape expulsion by their host’s immune system, pathogenic nematodes exploit regulatory pathways that are intrinsic parts of the mammalian immune system, such as regulatory T cells (Tregs). Using depletion of Treg mice, we showed that Foxp3+ Treg numbers increased rapidly during infection with the nematode Strongyloides ratti. Transient depletion of Tregs during the first days of infection led to dramatically reduced worm burden and larval output, without aggravation of immune pathology. The transient absence of Tregs during primary infection did not interfere with the generation of protective memory. Depletion of Tregs at later time points of infection (i.e., day 4) did not improve resistance, suggesting that Tregs exert their counterregulatory function during the priming of S. ratti-specific immune responses. Improved resistance upon early Treg depletion was accompanied by accelerated and prolonged mast cell activation and increased production of types 1 and 2 cytokines. In contrast, the blockade of the regulatory receptor CTLA-4 specifically increased nematode-specific type 2 cytokine production. Despite this improved immune response, resistance to the infection was only marginally improved. Taken together, we provide evidence that Treg expansion during S. ratti infection suppresses the protective immune response to this pathogenic nematode and, thus, represents a mechanism of immune evasion.

Section: Increased Immune Response In the Absence Of Tregsmentioning

confidence: 99%

Strongyloides ratti Infection Induces Expansion of Foxp3+ Regulatory T Cells That Interfere with Immune Response and Parasite Clearance in BALB/c Mice

Blankenhaus

Klemm

Eschbach

et al. 2011

“…Differences in dependency on IL-5 have been reported between primary and secondary immune responses. Studies with S. ratti showed a dependency upon IL-5 for protection from the primary infection, but not against a challenge infection (19). In contrast, IL-5 was shown to be essential for vaccination-induced protection against the filarial nematode Litosomoides sigmodontis, yet had no role during the primary response (20).…”

mentioning

confidence: 98%

“…Conversely, a role for IL-5 has been established in protective immunity against the nematodes Onchocerca volvulus (15), Onchocerca lienalis (16), Angiostrongylus cantonensis (17), Strongyloides stercoralis (18), and Strongyloides ratti (19). These nematodes showed an increased parasite burden, delayed expulsion, or impaired clearance of infection when the levels of IL-5 were reduced by treatment with the mAb TRFK-5.…”

mentioning

confidence: 99%

Role of IL-5 in Innate and Adaptive Immunity to LarvalStrongyloides stercoralisin Mice

Herbert

Lee

et al. 2000

113

110

Protective immunity to Strongyloides stercoralis infective larvae in mice has been shown to be dependent on IL-5 based on mAb depletion studies. The goal of this study was to determine the functional role of IL-5 during the innate and adaptive immune response to larval S. stercoralis in mice. In these studies, three strains of mice were used: wild-type C57BL/6J (WT), IL-5 knockout (KO), and IL-5 transgenic (TG). Innate responses to the larvae indicated that there was enhanced survival in the KO animals and decreased survival in the TG animals compared with WT. Furthermore, killing of larvae in TG mice was associated with eosinophil infiltration and degranulation. In studying the adaptive immune response, it was observed that immunization of KO mice did not lead to the development of protective immunity. Experiments were then performed to determine whether KO mice reconstituted with Abs or cells could then develop protective immunity. KO mice displayed protective immunity via a granulocyte-dependent mechanism following injection of purified IgM from immune wild-type animals. Immunity in KO mice could also be reconstituted by the injection of eosinophils at the time of immunization. These eosinophils did not participate in actively killing the challenge infection, but rather were responsible for the induction of a protective Ab response. We conclude that IL-5 is required in the protective immune response for the production of eosinophils, and that eosinophils were involved in larval killing during innate immunity and in the induction of protective Abs in the adaptive immune response.

“…A commonly used disease model to understand MC and eosinophil development in the mouse is the transient, T cell-dependent eosinophilia and mastocytosis that occurs in the intestines of helminth-infected mice and rats (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). In the jejunum of these helminth-infected animals, IL-5 plays a central role in the eosinophilia (11,17), whereas c-kit ligand, IL-3, IL-4, IFN-␥, and TNF-␣ play central roles in the mastocytosis (9,12,13,16,18). Other T cell-derived factors such as IL-9 (19 -21) are needed to instruct the expanded population of MCs in the jejunal epithelium to produce mouse MC protease-1 (mMCP-1), mMCP-2 (14,(22)(23)(24), and other mediators.…”

mentioning

confidence: 99%

Senescent Jejunal Mast Cells and Eosinophils in the Mouse Preferentially Translocate to the Spleen and Draining Lymph Node, Respectively, During the Recovery Phase of Helminth Infection

Friend¹,

Gurish

Austen

et al. 2000

Because mice infected with Trichinella spiralis experience a pronounced, but transient, mastocytosis and eosinophilia in their intestine, this disease model was used to follow the fate of senescent T cell-dependent mast cells (MCs) and eosinophils. Very few MCs or eosinophils undergoing apoptosis were found in the jejunum during the resolution phase of the infection, even though apoptotic MCs were common in the large intestine. Although the mesenteric draining lymph nodes contained large numbers of apoptotic eosinophils, MCs were rarely found at this location. During the recovery phase, large numbers of MCs were present in the spleen, and many of these cells possessed segmented nuclei. These splenic MCs were not proliferating. Although MCs from the jejunum and spleen of noninfected mice failed to express mouse MC protease (mMCP) 9, essentially all of the MCs in the jejunal submucosa and spleen of T. spiralis-infected mice expressed this serine protease during the recovery phase. The MCs in the jejunum expressed mMCP-9 before any mMCP-9-containing cells could be detected in the spleen. The fact that mMCP-9-containing MCs were detected in splenic blood vessels as these cells began to disappear from the jejunum supports the view that many jejunal MCs translocate to the spleen during the recovery phase of the infection. During this translocation process, some senescent jejunal MCs undergo nuclear segmentation. These studies reveal for the first time different exit and disposal pathways for T cell-dependent eosinophils and MCs after their expansion in the jejunum during a helminth infection.