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The lung is an important site for priming CD4 T-cell-mediated protective immunity against gastrointestinal helminth parasites.

ABSTRACT: The rodent hookworm Nippostrongylus brasiliensis typically infects its host by penetrating the skin and rapidly migrating to the lungs and gut. Following primary infection, immunocompetent mice become highly protected from reinfection with N. brasiliensis, with the numbers of worms gaining access to the lungs and gut being reduced by up to 90%. We used green fluorescent protein/interleukin-4 (IL-4) reporter mice and truncated infection studies to identify both the tissue site and mechanism(s) by which the host protects itself from reinfection with N. brasiliensis. Strikingly, we demonstrated that the lung is an important site for priming immune protection. Furthermore, a lung-initiated, CD4 T-cell-dependent, and IL-4- and STAT6-dependent response was sufficient to confer protection against reinfection. In conclusion, vaccination strategies which seek to break the cycle of reinfection and egg production by helminths such as hookworms can include strategies which directly stimulate Th2 responses in the lung.

SUBMITTER: Harvie M

PROVIDER: S-EPMC2937440 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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The lung is an important site for priming CD4 T-cell-mediated protective immunity against gastrointestinal helminth parasites.

Harvie Marina M Camberis Mali M Tang Shiau-Choot SC Delahunt Brett B Paul William W Le Gros Graham G

Infection and immunity 20100706 9

The rodent hookworm Nippostrongylus brasiliensis typically infects its host by penetrating the skin and rapidly migrating to the lungs and gut. Following primary infection, immunocompetent mice become highly protected from reinfection with N. brasiliensis, with the numbers of worms gaining access to the lungs and gut being reduced by up to 90%. We used green fluorescent protein/interleukin-4 (IL-4) reporter mice and truncated infection studies to identify both the tissue site and mechanism(s) by ...[more]

PMID: 20605978

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Project description:BackgroundType 2 immunity can be modulated by regulatory T (Treg) cell activity. It has been suggested that the deubiquitinase cylindromatosis (CYLD) plays a role in the development or function of Treg cells, implying that it could be important for normal protective immunity, where type 2 responses are prevalent.ObjectiveWe sought to investigate the role of CYLD in Treg cell function and TH2 cell immune responses under steady-state conditions and during helminth infection.MethodsFoxp3-restricted CYLD conditional knockout (KO) mice were examined in mouse models of allergen-induced airway inflammation and Nippostrongylus brasiliensis infection. We performed multiplex magnetic bead assays, flow cytometry, and quantitative PCR to understand how a lack of CYLD affected cytokine production, homing, and suppression in Treg cells. Target genes regulated by CYLD were identified and validated by microarray analysis, coimmunoprecipitation, short hairpin RNA knockdown, and transfection assays.ResultsTreg cell-specific CYLD KO mice showed severe spontaneous pulmonary inflammation with increased migration of Treg cells into the lung. CYLD-deficient Treg cells furthermore produced high levels of IL-4 and failed to suppress allergen-induced lung inflammation. Supporting this, the conditional KO mice displayed enhanced protection against N brasiliensis infection by contributing to type 2 immunity. Treg cell conversion into IL-4-producing cells was due to augmented mitogen-activated protein kinase and nuclear factor κB signaling. Moreover, Scinderin, a member of the actin-binding gelsolin family, was highly upregulated in CYLD-deficient Treg cells, and controlled IL-4 production through forming complexes with mitogen-activated protein kinase kinase/extracellular receptor kinase. Correspondingly, both excessive IL-4 production in vivo and the protective role of CYLD-deficient Treg cells against N brasiliensis were reversed by Scinderin ablation.ConclusionsOur findings indicate that CYLD controls type 2 immune responses by regulating Treg cell conversion into TH2 cell-like effector cells, which potentiates parasite resistance.

Dataset Information

The lung is an important site for priming CD4 T-cell-mediated protective immunity against gastrointestinal helminth parasites.

Publications

The lung is an important site for priming CD4 T-cell-mediated protective immunity against gastrointestinal helminth parasites.

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