Introduction
Helminth infection elicits a Type 2 inflammatory response that is required for worm expulsion and repair of worm-induced tissue damage. The Type 2 immune response involves the activation of innate immune cells including basophils, eosinophils, mast cells, and group 2 innate lymphoid cells (ILC2s), the polarization of CD4+ T helper type 2 (Th2) cells that produce interleukin (IL)-4, IL-5, IL-9, and IL-13, and extensive tissue remodeling (1-8).
For decades, immunologists have successfully leveraged genetic differences in various inbred mouse strains to better understand the factors that regulate Type 2 inflammation (2, 9-13). The response to the murine model for whipworm infection, Trichuris muris (9, 13, 14) is dependent upon the genetic background in inbred mouse strains. C57BL/6 and Balb/C mice mount a robust Type 2 response and can expel parasites after infection with a high dose of eggs, while other strains such as AKR mice do not mount a fulminant Type 2 response, cannot clear worms, and harbor a chronic infection (9, 11, 13-17). These strain-dependent differences in outcome have revealed numerous cellular players and pathways that are required for a robust Type 2 immune response and resistance to T. muris infection observed in C57BL/6 but not AKR mice (9, 11, 13-17). Thus, genetically inbred mice offer an avenue to assess how particular cell types are activated in helminth infection and how these cells might contribute to resistance.
Our group and others have recently shown that basophils are important in mounting an effective Type 2 inflammatory response that expels T. muris in C57BL/6 mice (7, 18, 19). Basophils are rare innate granulocytes that comprise <1% of immune cells (20-22). In C57BL/6 mice, basophils are critical players in Type 2 inflammation, supporting worm clearance and the response to allergens in the context of allergic disease. Upon activation, basophils release inflammatory mediators, including histamine, proteoglycans, lipid mediators, proteases, growth factors, chemokines, and cytokines that promote Type 2 immunity. Basophils are activated by IgE crosslinking of the high affinity IgE receptor (Fcεr1α), stimulation with cytokines like thymic stromal lymphopoietin (TSLP), IL-33, and IL-3, and signaling through the Notch pathway (20-29), a receptor-ligand-based cell-cell communication pathway that can broadly regulate gene expression in a variety of contexts and cell types (30). Our previous data showed that basophils upregulated Notch2 during infection and that basophil effector gene expression and tissue positioning and fulminant Type 2 responses, but not basophil population expansion, were dependent on basophil-intrinsic Notch (7). These data reveal that Notch signaling is an important factor in basophil effector function during helminth infection in C57BL/6 mice. However, how Notch responsiveness in basophils is regulated in vivo , and how basophil responses differ in various genetically inbred mouse strains is unclear.
Here, we use AKR/J mice that are Th1-skewed and susceptible to T. muris (9-13, 15) to assess how basophil responses and Notch expression by basophils are regulated in a genetically susceptible inbred mouse strain. Upon T. muris infection in AKR/J mice, there was an infection-induced basophil population expansion in the cecum and spleen, similar to that observed in resistant C57BL/6 mice. Expression of genes associated with basophil as well as mast cell activation and serum IgE levels were also increased in AKR mice, despite a Type 1-skewed inflammatory response that was associated with persistent infection. However, basophils in AKR/J mice did not upregulate surface expression of the Notch2 receptor after infection, which we previously have shown occurs in C57BL/6 mice (7). Neutralization of the Type 1 cytokine IFN-γ in infected AKR/J mice (31) did not result in Notch2 receptor upregulation on basophils at day 14 post-infection (p.i.), suggesting that the Type 1 skewed response in AKR/J mice is not a primary factor that controls Notch2 expression in AKR/J basophils. Together, these data reveal that basophilia is a hallmark feature of T. murisinfection even in genetically susceptible AKR/J mice and that differences in genetic background, not IFN-γ levels, may contribute to basophil regulation of Notch receptor expression in AKR/J mice.