Environmental enteric dysfunction induces regulatory T cells that inhibit local CD4+ T cell responses and impair oral vaccine efficacy

Bhattacharjee, Amrita; Burr, Ansen H.P.; Overacre-Delgoffe, Abigail; Tometich, Justin T.; Yang, Deyi; Huckestein, Brydie R.; Linehan, Jonathan L.; Spencer, Sean P.; Hall, Jason A.; Harrison, Oliver J.; Fonseca, Denise Morais da; Norton, Elizabeth B.; Belkaid, Yasmine; Hand, Timothy W.

doi:10.1016/j.immuni.2021.07.005

Cited by 42 publications

(33 citation statements)

References 99 publications

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“…Chronic parasitic infection in mice with the systemic, blood-borne, filarial helminth Litmosomoides sigmodontis induces an expansion of splenic, Foxp3 - IL-10 + , T regulatory 1 (Tr1) cells and reduces the quantity and quality of influenza vaccine-specific antibody responses (83). In an environmental enteric dysfunction model comprised of severely malnourished mice chronically infected with adherent E. coli , LP-resident Foxp3 + RORγT + Tregs were associated with impaired antibody responses to an oral heat labile toxin vaccine (84). Our data demonstrate that neither a systemic chronic infection, nor severe malnutrition is required for the expansion of infection-associated regulatory T cells and suppressed vaccine-specific antibody responses.…”

Section: Discussionmentioning

confidence: 99%

Intestinal helminth infection impairs oral and parenteral vaccine efficacy

Hardy

Kapita²,

Campbell

et al. 2022

Preprint

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The impact of endemic parasitic infection on vaccine efficacy is an important consideration for vaccine development and deployment. We have examined whether intestinal infection with the natural murine helminth Heligmosomoides polygyrus bakeri alters antigen-specific antibody and cellular immune responses to oral and parenteral vaccination in mice. We found that oral vaccination of mice with a clinically relevant, live, attenuated, recombinant Salmonella vaccine that expresses chicken egg ovalbumin (Salmonella-OVA) disrupts ovalbumin-specific regulatory T cell networks in the gut associated lymphoid tissue and promotes T-effector responses to OVA. Chronic intestinal helminth infection significantly reduced Th1-skewed antibody responses to oral vaccination with Salmonella-OVA. Activated, adoptively-transferred, OVA-specific CD4+ T cells accumulated in draining mesenteric lymph nodes (MLN) of vaccinated mice, irrespective of their helminth-infection status. However, helminth infection increased the frequencies of adoptively-transferred OVA-specific CD4+ T cells producing IL-4 and IL-10 in the MLN. Chronic intestinal helminth infection also significantly reduced Th2-skewed antibody responses to parenteral vaccination with OVA adsorbed to alum. These findings suggest helminth-induced impairment of vaccine antibody responses may be driven by the development of IL-10-secreting CD4+ T regulatory cells. They also underscore the potential need to treat parasitic infection before mass vaccination campaigns in helminth-endemic areas.

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Section: Discussionmentioning

confidence: 99%

Intestinal helminth infection impairs oral and parenteral vaccine efficacy

Hardy

Kapita²,

Campbell

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Interestingly, the microbiome and its metabolites were identified as critical factors that directly affect the activity of surrounding immune cells [85] . In addition, the effectiveness of oral vaccines was reported to be lowered by regulatory T cells induced under an abnormal intestinal environment, such as those associated with chronic malnutrition or environmental enteric dysfunction [86] . Therefore, future efforts to develop oral vaccines should consider the role of the microbiome and inflammatory pathological conditions when seeking to maximize the immune efficacy.…”

Section: Impact Of the Delivery Routes On The In Vivo Fates Of Vaccinesmentioning

confidence: 99%

In vivo fate and intracellular trafficking of vaccine delivery systems

Lee

Kim

Byun

et al. 2022

Advanced Drug Delivery Reviews

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“…Likewise, in CRC patients TCF-1 low Treg cells and elevated Th17 immunity were found ( 138 ). In a mouse model of environmental enteric dysfunction (EED), a gastrointestinal inflammatory disease caused by malnutrition and chronic infection, Hand and colleagues recently reported that mice with EED harbor increased RORγt+ Treg cells in the small intestine, contributing to poor efficacy of oral vaccines ( 139 ). Deletion of RORγt expression in Treg cells was sufficient to restore small intestinal vaccine specific CD4 T cell responses and vaccine induced protection, suggesting a detrimental role of Treg cells.…”

Section: Subsets Of Tissue Resident Treg Cells: Characteristics and F...mentioning

confidence: 99%

“…Deletion of RORγt expression in Treg cells was sufficient to restore small intestinal vaccine specific CD4 T cell responses and vaccine induced protection, suggesting a detrimental role of Treg cells. However, the lack of these Treg cells was associated with enhanced susceptibility to EED ( 139 ). These findings highlight the complex and diverse mechanisms mediated by intestine TR-Treg cells in different disease settings.…”

Section: Subsets Of Tissue Resident Treg Cells: Characteristics and F...mentioning

confidence: 99%

Tissue Resident Foxp3+ Regulatory T Cells: Sentinels and Saboteurs in Health and Disease

2022

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Foxp3+ regulatory T (Treg) cells are a CD4 T cell subset with unique immune regulatory function that are indispensable in immunity and tolerance. Their indisputable importance has been investigated in numerous disease settings and experimental models. Despite the extensive efforts in determining the cellular and molecular mechanisms operating their functions, our understanding their biology especially in vivo remains limited. There is emerging evidence that Treg cells resident in the non-lymphoid tissues play a central role in regulating tissue homeostasis, inflammation, and repair. Furthermore, tissue-specific properties of those Treg cells that allow them to express tissue specific functions have been explored. In this review, we will discuss the potential mechanisms and key cellular/molecular factors responsible for the homeostasis and functions of tissue resident Treg cells under steady-state and inflammatory conditions.

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Environmental enteric dysfunction induces regulatory T cells that inhibit local CD4+ T cell responses and impair oral vaccine efficacy

Cited by 42 publications

References 99 publications

Intestinal helminth infection impairs oral and parenteral vaccine efficacy

Intestinal helminth infection impairs oral and parenteral vaccine efficacy

In vivo fate and intracellular trafficking of vaccine delivery systems

Tissue Resident Foxp3+ Regulatory T Cells: Sentinels and Saboteurs in Health and Disease

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