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.