Th2-associated responses and their control in parasitic helminth infections and related disorders

National Institute Of Allergy And Infectious Diseases

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Abstract

To investigate the heterogeneity of Th2 effectors subsets known to be expanded helminth-infected/HDM-sensitized patients (and various control subject cohorts), we characterized their phenotype and function using multiparameter 28-color panel flow cytometry. We identified 3 novel subsets driven by helminth infection and/or allergic sensitization based on a self-organizing map tool ). These 3 CD4+ subsets are described more fully in the accompanying figure To explore the mechanisms underlying the hyperreactive CD4+ response seen in filarial infected/HDM sensitized patients, we developed a murine model for asthmatic inflammation using HDM intranasal sensitization followed by infection with the roundworm Ascaris. We were able to show that environmental aeroallergens drive a lung-specific eosinophil-rich type-2-immune response that leads to arrested Ascaris larval development and markedly reduced lung parasite numbers. This effect is dependent on the presence of eosinophils, as eosinophil-deficient mice were unable to limit parasite development or numbers. We then demonstrated that the HDM-induced immunity to Ascaris parasites is dependent on eosinophils driven by CD4+ T cells. We then investigated the role of tissue-resident Th2 cells in a type-2 pulmonary inflammation using the same model(s). RNA extracted from HDM-sensitized lungs and from lungs following infection with Ascaris larval stages revealed distinct transcriptional profiles with marked upregulation in genes associated with Th2 activation pathways including IL-5 and IL-13. Through a series of experiments, our data now suggest that allergen-driven Th2 cell-derived IL-5 and IL-13 are key players in the tissue protective immunity against helminth larval stages through the control of tissue eosinophils numbers. This effect is dependent on eosinophils triggered by innate immunity signaling on IL-13Ra1 in the lung, as allergen sensitized-IL-13Ra1 deficient mice were unable to limit parasite development or numbers. To explore further the role played by Th2 cells (and in particular the IL-13/IL-13R signaling axis) in mediating this eosinophil-dependent phenomenon, we show that in HDM-sensitized-IL-13Ra1 deficient mice, there was a dramatic suppression in the production of CCL11 (eotaxin-1) and CCL24 (eotaxin-2) levels, resulting in a significant reduction in lung tissue eosinophil frequency and numbers; as a consequence the mice failed to limit Ascaris larvae development. Moreover, in vivo administration of neutralizing antibodies to CD4 or the adoptive transfer of CD4+ T cells from IL-5-deficient mice to TCR-a knockout mice prior to HDM sensitization significantly impaired the HDM-specific type-2-immune response, diminishing markedly the HDM-specific antibody response, mucus production and the numbers of allergen-driven eosinophils in the lungs that in turn allowed normal larval development when compared to appropriate control mice. Taken together, our data suggest that HDM-induced inflammation drives an eosinophil-dependent helminth larval arrest/killing in the lung mediated by a pulmonary-resident IL-5 producing Th2 cells and IL-13/IL-13Ra1 signaling in the lung epithelia. To identify the molecular basis for this allergen/helminth interaction, we were able to show that HDM sensitization drives marked IgE and IgG1 antibody responses that cross-react with Ascaris larval antigens. We then identified (through targeted proteomics) the 2 major Ascaris-encoded HDM homologues based on high sequence and structural similarity, a finding suggesting that aeroallergen sensitization drives helminth reactive antibodies through molecular and structural cross reactivity that in turn drives allergic inflammation.