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Mast cells (MCs) are potent inflammatory cells that are distributed throughout mucosal barrier tissues and respond rapidly to pathogenic stimuli. During helminth infections, MCs play an important role as late-stage effectors. However, it is currently unknown whether MCs contribute to the early innate events that determine the priming of adaptive immunity. MC-deficient mouse strains and mice treated with the MC stabilizing agent cromolyn sodium had dramatically reduced Th2 priming and type 2 cytokine production and harbored increased parasite burdens following infection with gastrointestinal helminths (Heligmosomoides polygyrus bakeri and Trichuris muris). In addition, early production of the tissue-derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) was significantly diminished in MC-deficient mice and resulted in decreased numbers of infection-elicited IL-25-dependent (Lin(-)CD45(-))CD34(+)Sca-1(+) progenitors, which produced type 2 cytokines and could be differentiated into mast cells ex vivo. Finally, repair of MC deficiency increased production of IL-25, IL-33, and TSLP, restored progenitor cell numbers and Th2 priming, and reduced parasite burden. Our data reveal an innate IgE-independent role for MCs in orchestrating type 2 immune responses via the regulation of IL-25, IL-33, and TSLP.

The vitamin D receptor participates in the control of IgE class-switch recombination in B cells. The physiologic vitamin D receptor agonist, 1,25(OH)2D3 (calcitriol), is synthesized by the essential enzyme 25-hydroxyvitamin D3-1α-hydroxylase (CYP27B1), which can be expressed by activated immune cells. The role of endogenous calcitriol synthesis for the regulation of IgE has not been proven. In this study, we investigated IgE-responses in Cyp27b1-knockout (KO) mice following sensitization to OVA or intestinal infection with Heligmosomoides polygyrus. Specific Igs and plasmablasts were determined by ELISA and ELISpot, Cyp27b1 expression was measured by quantitative PCR. The data show elevated specific IgE and IgG1 concentrations in the blood of OVA-sensitized Cyp27b1-KO mice compared with wild-type littermates (+898 and +219%). Accordingly, more OVA-specific IgG1-secreting cells are present in spleen and fewer in the bone marrow of Cyp27b1-KO mice. Ag-specific mechanisms are suggested as the leucopoiesis is in general unchanged and activated murine B and T lymphocytes express Cyp27b1. Accordingly, elevated specific IgE concentrations in the blood of sensitized T cell-specific Cyp27b1-KO mice support a lymphocyte-driven mechanism. In an independent IgE-inducing model, i.e., intestinal infection with H. polygyrus, we validated the increase of total and specific IgE concentrations of Cyp27b1-KO compared with wild-type mice, but not those of IgG1 or IgA. We conclude that endogenous calcitriol has an impact on the regulation of IgE in vivo. Our data provide genetic evidence supporting previous preclinical and clinical findings and suggest that vitamin D deficiency not only promotes bone diseases but also type I sensitization. [ABSTRACT FROM AUTHOR]

Immunity to intestinal nematodes requires CD4⁺ Th2-cell responses, including IL-4 and IL-13 production. Chronic infection with intestinal nematodes leads to downregulation of these responses, and few functional T helper (Th) 2 cells are detected in secondary lymphoid organs in the chronic phase or after abrogation of infection. Here, we show with a natural murine infection with Heligmosomoides polygyrus that highly functional memory Th2 cells persist in the lamina propria and in addition in the peritoneal cavity (PC) after abrogation of infection. While both tissue-resident memory (TRM) populations proliferate in situ and express IL-4, IL-5, and IL-13 upon TCR-dependent stimulation, only peritoneal memory cells express high levels of the IL-33 receptor and produce IL-5 and IL-13 upon TCR-independent stimulation with IL-33 and IL-7. Most importantly, PC-derived TRM cells are able to mediate anti-helminthic effects by decreasing the fecundity of female worms upon transfer into recipient mice. These results show that nonlymphoid compartments can serve as reservoirs for Th2 memory cells, and furthermore that innate effector function of Th2 memory cells is restricted to CD4⁺ memory T cells residing in the PC. [ABSTRACT FROM AUTHOR]

The stable lineage commitment of naïve T helper cells to a hybrid Th1/2 phenotype reveals the cell-intrinsic reconciliation of two opposing T cell differentiation programs and provides a self-limiting mechanism to dampen immunopathology. [ABSTRACT FROM AUTHOR]