Regulation of type 2 immunity to helminths by mast cells

Abstract

Recently, we demonstrated a novel role for gastrointestinal mast cells (MCs) in the early events that lead to the generation of Th2 immunity to helminth infection. Mice lacking MCs (Kit(W) /Kit(W-v) and Kit(W-Sh)) showed a significant inhibition of Th2 cell priming following infection with the parasitic helminth Heligmosomoides polygyrus bakeri (Hp). We showed that MCs degranulate during the early stages of infection when the helminth larvae invade the small intestinal tissue. Furthermore, MC degranulation was required for the enhanced expression and production of the tissue-derived cytokines IL-25, IL-33 and TSLP, which are required for the optimal orchestration and priming of type 2 immunity. In this addendum we aim to address several questions raised by our findings - in particular, the mechanisms through which MCs may recognize helminth exposure in the early stages of infection and by which they may enhance expression of critical tissue cytokines thus, enabling Th2 priming. Furthermore, we will discuss these findings in the context of recently described novel innate immune cells, such as type 2 hematopoietic progenitors and type 2 innate lymphoid cells.

Figure 1. Potential mechanisms of IgE-independent mast cell activation and tissue-derived cytokine induction during intestinal helminth infection. Activation (Left panel): Helinth derived antigens, immunomodulators and proteases along with concurrent stimulation by commensal derived molecules and/or dangers signals can be recognized by mast cells through a variety or receptors including Toll-like receptors (TLRs), NOD-like receptors (NLRs) and “alarmin” receptors (e.g., IL-33R). Response (Right panel): Following stimulation mast cells respond via degranulation and/or the synthesis of cytokines, possibly include IL-25, IL-33 and TSLP. Moreover, mast cell inflammatory mediators have the ability to cross talk with other cells, such as epithelial cells, to induce the production of tissue-derived cytokines that are ultimately required for the optimal orchestration, amplification and priming of Th2 responses toward gastrointestinal helminths.

Figure 2. Type 2 innate lymphoid cells are rare in the MLN during the early stages of Hp infection but can be induced by exogenous rIL-25 treatment. C57BL/6 mice were infected with 200 Hp L3 and Mesenteric Lymph Node (MLN) derived lymphocytes isolated and stained for a population resembling type 2 innate lymphoid cells via flow cytometry. A) Total numbers of type 2 innate lymphoid cells were quantified at day 6 post infection (p.i.) in the MLN of WT (black bars) and mast cell deficient Kit^W/Kit^W-v mice (white bars) following Hp infection alone or Hp infection with rIL-25 treatment (0.4μg i.p. on days 0–4 p.i.). B) Cells were gated as low/negative for a lineage cocktail (CD3/CD4/CD19/CD11b/CD11c) (shaded gate) and expressed the surface markers ST-2 (IL-33R), CD127 (IL-7Rα), ICOS and were c-kit low/int. C) Expression of IL-13 in Lineage low/negative gated ST-2+ or ST-2- populations in Hp infected, rIL-25 treated mice. Data are representative of two independent experiments with n = 4–6 mice per group.