Parasite Proximity Drives the Expansion of Regulatory T Cells in Peyer's Patches following Intestinal Helminth Infection

Mosconi, Ilaria; Dubey, Lalit Kumar; Volpe, Beatrice; Bieren, Julia Esser‐von; Zaiss, Mario M.; Lebon, Luc; Massacand, Joanna; Harris, Nicola L.

doi:10.1128/iai.00266-15

Cited by 27 publications

(29 citation statements)

References 47 publications

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“…Consistent with previous studies, there were significant increases in Th2 cytokines as well as IL-6 compared to isotype control, infected Irf8 -/- mice, but there were no effects on the adult worm burden or the numbers of CD4 + GATA3 + T cells or AAMØ [35, 38, 39]. Interestingly, egg production was significantly increased in Treg-depleted compared to isotype control Irf8 -/- mice indicating increased worm fecundity in the depleted mice, but the basis of the increase is not clear.…”

Section: Discussionsupporting

confidence: 89%

“…Previous studies indicate that Foxp3 + Tregs expand in local lymphoid tissues, including the lamina propria, Peyer’s patches, and MLN, as well as systemically in the spleen of Hpb-infected B6 and BALB/c mice [34, 35, 38]. Although Foxp3 + Tregs contribute to suppressed Th2 cytokine responses during Hpb infection, their effect on adult worm expulsion is variable [35, 39].…”

Section: Discussionmentioning

confidence: 99%

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IRF-8 regulates expansion of myeloid-derived suppressor cells and Foxp3+ regulatory T cells and modulates Th2 immune responses to gastrointestinal nematode infection

et al. 2017

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Interferon regulatory factor-8 (IRF-8) is critical for Th1 cell differentiation and negatively regulates myeloid cell development including myeloid-derived suppressor cells (MDSC). MDSC expand during infection with various pathogens including the gastrointestinal (GI) nematode Heligmosomoides polygyrus bakeri (Hpb). We investigated if IRF-8 contributes to Th2 immunity to Hpb infection. Irf8 expression was down-regulated in MDSC from Hpb-infected C57BL/6 (B6) mice. IRF-8 deficient Irf8-/- and BXH-2 mice had significantly higher adult worm burdens than B6 mice after primary or challenge Hpb infection. During primary infection, MDSC expanded to a significantly greater extent in mesenteric lymph nodes (MLN) and spleens of Irf8-/- and BXH-2 than B6 mice. CD4+GATA3+ T cells numbers were comparable in MLN of infected B6 and IRF-8 deficient mice, but MLN cells from infected IRF-8 deficient mice secreted significantly less parasite-specific IL-4 ex vivo. The numbers of alternatively activated macrophages in MLN and serum levels of Hpb-specific IgG1 and IgE were also significantly less in infected Irf8-/- than B6 mice. The frequencies of antigen-experienced CD4+CD11ahiCD49dhi cells that were CD44hiCD62L- were similar in MLN of infected Irf8-/- and B6 mice, but the proportions of CD4+GATA3+ and CD4+IL-4+ T cells were lower in infected Irf8-/- mice. CD11b+Gr1+ cells from naïve or infected Irf8-/- mice suppressed CD4+ T cell proliferation and parasite-specific IL-4 secretion in vitro albeit less efficiently than B6 mice. Surprisingly, there were significantly more CD4+ T cells in infected Irf8-/- mice, with a higher frequency of CD4+CD25+Foxp3+ T (Tregs) cells and significantly higher numbers of Tregs than B6 mice. In vivo depletion of MDSC and/or Tregs in Irf8-/- mice did not affect adult worm burdens, but Treg depletion resulted in higher egg production and enhanced parasite-specific IL-5, IL-13, and IL-6 secretion ex vivo. Our data thus provide a previously unrecognized role for IRF-8 in Th2 immunity to a GI nematode.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

IRF-8 regulates expansion of myeloid-derived suppressor cells and Foxp3+ regulatory T cells and modulates Th2 immune responses to gastrointestinal nematode infection

et al. 2017

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“…Primary H. polygyrus bakeri infection induces Foxp3 þ Tregs in intestinal tissue as well as in the MLN and spleen, but the reported effect of depletion of these cells on worm expulsion and intestinal pathology is variable. 37,[42][43][44][45] However, these studies consistently showed that depletion of Tregs results in increased Th2 responses. Furthermore, it appears that there is no correlation between susceptibility to primary H. polygyrus bakeri infection and the number of tissue Foxp3 þ Tregs among inbred mouse strains although the suppressive potential of cells from mice with varying levels of susceptibility was not examined.…”

Section: Discussionmentioning

confidence: 99%

Primary Heligmosomoides polygyrus bakeri infection induces myeloid-derived suppressor cells that suppress CD4+ Th2 responses and promote chronic infection

et al. 2017

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Primary infection with the gastrointestinal nematode Heligmosomoides polygyrus bakeri is chronic in C57BL/6 (B6) mice whereas challenge infection is rapidly eliminated. F4/80CD11bGr cells, presumed to be neutrophils, were reported to accumulate around encysting larvae in intestinal tissue during primary infection, but their exact identity and role remain unclear. We observed significant increases in F4/80CD11bGr1 cells in mesenteric lymph nodes (MLNs) and spleen after primary but not challenge infection; a high proportion of these cells expressed Ly6G and Ly6C. These cells, which phenotypically resemble myeloid-derived suppressor cells (MDSC), increased in lamina propria (LP) early during primary infection. Increased MDSC were associated with low numbers of alternatively activated macrophages (AAMØ) in LP and CD4GATA3 T cells and AAMØ in MLN and spleen. Purified CD11cCD11bGr1 cells from H. polygyrus bakeri-infected mice suppressed OVA-specific CD4 T-cell proliferation via a nitric oxide-dependent mechanism and parasite-specific IL-4 secretion in vitro. Adoptive transfer of CD11cCD11bGr1 cells from mice with primary infection resulted in significantly higher adult worm burdens and increased egg production in naïve B6 recipients infected with H. polygyrus bakeri. Altogether, these findings indicate that primary H. polygyrus bakeri infection induces a novel subset of MDSC that suppress CD4 Th2 responses and promote chronic infection.

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“…Both factors contribute to extensive cell death, experimentally, when isolating leukocytes from the small intestine for further analysis. Published studies therefore typically concentrate on earlier time-points or on cells located in active lymphoid tissues (Mosconi et al, 2015;Pelly et al, 2016;Perona-Wright et al, 2010). Furthermore, larger immune cells such as macrophages frequently become trapped in mucus and dying tissues and are therefore very difficult to isolate.…”

Section: Introductionmentioning

confidence: 99%

Isolation and functional characterisation of lamina propria leukocytes from helminth-infected, murine small intestine

Webster

Andrusaite

Shergold

et al. 2019

Preprint

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The use of helminth infections as tools to understand the type 2 immune response is a well-established technique and important to many areas of immunological research. The phenotype and function of immune cell populations at the site of infection is a key determinant of pathogen clearance. However, infections with helminths such as the murine nematode Heligomosmoides polygryrus cause increased mucus production and thickening of the intestinal wall, which can result in extensive cell death when isolating and analysing cells from the lamina propria (LP). Populations of larger immune cells such as macrophages and dendritic cells are often trapped within mucus or dying tissues. Here we describe an optimised protocol for isolating LP leukocytes from the small intestine of H.polygyrus -infected mice, and we demonstrate phenotypic and functional identification of myeloid and CD4 + T cell subsets using cytokine staining and flow cytometry. Our protocol may provide a useful experimental method for the immunological analysis of the affected tissue site during helminth infections.

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Parasite Proximity Drives the Expansion of Regulatory T Cells in Peyer's Patches following Intestinal Helminth Infection

Cited by 27 publications

References 47 publications

IRF-8 regulates expansion of myeloid-derived suppressor cells and Foxp3+ regulatory T cells and modulates Th2 immune responses to gastrointestinal nematode infection

IRF-8 regulates expansion of myeloid-derived suppressor cells and Foxp3+ regulatory T cells and modulates Th2 immune responses to gastrointestinal nematode infection

Primary Heligmosomoides polygyrus bakeri infection induces myeloid-derived suppressor cells that suppress CD4+ Th2 responses and promote chronic infection

Isolation and functional characterisation of lamina propria leukocytes from helminth-infected, murine small intestine

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