Chronic immune activation associated with intestinal helminth infections results in impaired signal transduction and anergy

Borkow, Gadi; Leng, Qibin; Weisman, Z.; Stein, Miguel; Galai, Noya; Kalinkovich, Alexander; Bentwich, Zvi

doi:10.1172/jci10182

Cited by 193 publications

(168 citation statements)

References 47 publications

(38 reference statements)

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“…Third, immune activation (largely measured as increased expression of CD38 þ and HLA-DR þ on T-cells) has also been shown to be inversely correlated with IL-7Ra expression on CD4 T-cells in HIV-infected patients, 45,46 and immune activation has a negative impact on CD4 T-cell recovery. [47][48][49] Although we did not compare the immune activation levels in the UARTO and Caucasian patients, numerous studies have described a higher degree of immune activation both in HIVuninfected [50][51][52][53][54] and HIV-infected African patients [53][54][55][56] as compared with patients from high-income countries owing to differences in the environment 52 and prevalence of other co-infections. 51 The combined effects of poorer CD4 T-cell gain owing to increased T-cell activation and a reduced expression of IL-7Ra on T-cells may potentially negate any beneficial effects of increased IL-7 availability.…”

Section: Discussionmentioning

confidence: 95%

“…[47][48][49] Although we did not compare the immune activation levels in the UARTO and Caucasian patients, numerous studies have described a higher degree of immune activation both in HIVuninfected [50][51][52][53][54] and HIV-infected African patients [53][54][55][56] as compared with patients from high-income countries owing to differences in the environment 52 and prevalence of other co-infections. 51 The combined effects of poorer CD4 T-cell gain owing to increased T-cell activation and a reduced expression of IL-7Ra on T-cells may potentially negate any beneficial effects of increased IL-7 availability. We found that homozygous carriers of the G-allele at rs3194051 experienced faster time to CD4 T-cell 4500 cells ml À1 compared with homozygous carriers of the A-allele in the UARTO patients by using survival analysis, but there was no significant association by using LMM.…”

Section: Discussionmentioning

confidence: 95%

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The role of SNPs in the α-chain of the IL-7R gene in CD4+ T-cell recovery in HIV-infected African patients receiving suppressive cART

et al. 2011

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We previously found an association between faster CD4 þ T-cell recovery in HIV-infected patients receiving combination antiretroviral therapy (cART) and interleukin-7 receptor-a (IL-7Ra) haplotype-2 in a predominantly Caucasian cohort. This study aims to determine whether this association was also significant in Africans. Patients were recruited from the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort (n ¼ 352). We used survival analysis and linear mixed modelling (LMM) to determine factors associated with CD4 T-cell recovery. Eight IL-7Ra single-nucleotide polymorphisms (SNPs) were genotyped in both Africans and Caucasians (n ¼ 57). Soluble (s)IL-7Ra levels were measured by ELISA. In UARTO, IL-7Ra haplotype-2 was associated with slower CD4 T-cell recovery following cART by using survival analysis (P ¼ 0.020) and no association was found with LMM (P ¼ 0.958). The tagging-SNP for IL-7Ra haplotype-2 (rs6897932) was associated with decreased sIL-7Ra (Po0.001). The haplotypes for the IL-7Ra were significantly different in Africans and Caucasians. Using IL-7Ra genotypes we found slower CD4 T-cell recovery in UARTO patients was still associated with rs6897932 (P ¼ 0.009) and rs3194051 was associated with faster CD4 T-cell recovery (P ¼ 0.006). Unlike Caucasians, we did not demonstrate a significant association between IL-7Ra haplotype 2 and faster CD4 T-cell recovery in Africans. The IL-7Ra SNPs associated with CD4 T-cell recovery following cART differ in African and Caucasian cohorts.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 95%

The role of SNPs in the α-chain of the IL-7R gene in CD4+ T-cell recovery in HIV-infected African patients receiving suppressive cART

et al. 2011

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“…The role of CTLA-4 in parasitic infections has recently been explored in mouse models (31,32) and in some human studies (33). In this study we have begun to assess a possible role for this molecule in the T cell hyporesponsiveness observed in filaria-infected patients.…”

Section: Ctla-4 In Filarial Infectionsmentioning

confidence: 99%

CTLA-4 in Filarial Infections: Implications for a Role in Diminished T Cell Reactivity

Steel

Nutman

2003

The Journal of Immunology

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To determine the role that CTLA-4 might play in mediating the diminished parasite Ag-specific T cell responsiveness that is characteristically seen in filaria-infected patients, several study populations and methods were used. First, quantitative assessment of mRNA expression determined that PBMC from uninfected adolescents exposed in utero to microfilarial (Mf) Ag demonstrated a strong up-regulation of CTLA-4 to the Mf stage of the parasite in contrast to that observed in cells from children born of uninfected mothers (p = 0.005). Next, the frequency of CTLA-4 expression was examined using flow cytometry in cells from filaria-infected and -uninfected individuals ex vivo. Individuals born in filarial endemic regions of the world (with long-standing infections) had greater percentages of CD4+CTLA-4+ cells than did expatriate infected or uninfected individuals (p = 0.005 and 0.05, respectively); in addition, Mf+ patients demonstrated higher frequencies of CD4+CTLA-4+ and CD8+CTLA-4+ cells (p = 0.027 and 0.037, respectively) than did Mf− infected individuals. Of interest, the greatest intensity of CTLA-4 expression occurred in CD4+CD25+ cells, a population purported to include suppressor cells. Finally, in vitro blocking of CTLA-4 expression in PBMC from filaria-infected individuals induced a mean increase of 44% in IL-5 production to Mf Ag, whereas there was a concurrent mean decrease of 42% in IFN-γ production, suggesting that CTLA-4 also acts to alter the Th1/Th2 balance in filaria-infected individuals. Together, these data indicate a significant role for CTLA-4 in regulating the host response to filarial infections and that factors such as length of exposure and patency are important codeterminants.

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“…2016. 46: 1180-1192 Immunity to infection 1181 to be the result of the persistent contact of parasite antigen with immune cells during chronic helminth infection [7]. Anergenic T cells differ from Treg cells in that they do not express FoxP3 or produce IL-10 or TGF-β.…”

Section: Introductionmentioning

confidence: 99%

“…Studies involving S. mansoni show the enhanced expression of GRAIL is linked to the suppression of Th2 cells and also using a filarial nematode, CD4 + T cells become functionally unresponsive [11,12]. Other studies indicate that anergenic-like T cells are the result of helminth infections, with an increase in anergenic markers and T-cell suppression [13][14][15][16]. Fasciola hepatica causes chronic liver disease in both humans and ruminants globally, and is our model parasite to examine helminth-driven immune responses.…”

mentioning

confidence: 99%

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

Aldridge

O’Neill

2016

Eur J Immunol

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FoxP3 + Treg cells and anergic T cells are the two regulatory phenotypes of T-cell responses associated with helminth infection. Here, we examine the T-cell responses in mice duringKeywords: Anergy r C-type lectin receptors r Dendritic cells r Helminth infection r Host-pathogen interactions r Mannose receptor r T-cell responses Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionHelminth parasites can survive within their hosts for many years by suppressing T-cell driven protective immune responses and Th1/Th2-mediated pathology through the induction of regulatory networks that suppress inflammatory responses [1][2][3][4]. These regulatory networks include regulatory T cells (Treg) that in the context of helminth infection is widely understood. 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.Few studies have examined the role of anergenic T cells during helminth infection. The induction of this cell population is thought C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2016. 46: 1180-1192 Immunity to infection 1181 to be the result of the persistent contact of parasite antigen with immune cells during chronic helminth infection [7]. Anergenic T cells differ from Treg cells in that they do not express FoxP3 or produce IL-10 or TGF-β. Instead anergy is a hyporesponsive state with the failure of T cells to proliferate or produce cytokines when restimulated with antigens in vitro [8]. Anergic T cells do not secrete IL-2, a factor important for T-cell proliferation and effector responses. However, the addition of IL-2 can overcome this hyporesponsiveness, restoring helminth-driven T-cell responses. Gene analysis studies have identified a number of genes including Rnf128 (Grail), Itch, Egr2 and Egr3, and CblB that are involved in the induction and maintenance of T-cell anergy [9,10]. A number of helminth infections have shown T-cell anergy or Tcell hyporesponsiveness to be involved in immune suppression. Studies involving S. mansoni show the enhanced expression of GRAIL is linked to the suppression of Th2 cells and also using a filarial nematode, CD4 + T cells become functionally unresponsive [11,12]. Other studies indicate that anergenic-like T cells are the result of helminth infections, with an increase in anergenic markers and T-cell suppression [13][14][15][16]. Fasciola hepatica causes chronic liver d...

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Chronic immune activation associated with intestinal helminth infections results in impaired signal transduction and anergy

Cited by 193 publications

References 47 publications

The role of SNPs in the α-chain of the IL-7R gene in CD4+ T-cell recovery in HIV-infected African patients receiving suppressive cART

The role of SNPs in the α-chain of the IL-7R gene in CD4+ T-cell recovery in HIV-infected African patients receiving suppressive cART

CTLA-4 in Filarial Infections: Implications for a Role in Diminished T Cell Reactivity

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

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