Foxp3+ Regulatory T Cells Delay Expulsion of Intestinal Nematodes by Suppression of IL-9-Driven Mast Cell Activation in BALB/c but Not in C57BL/6 Mice

Accumulating evidence suggests that IL-9-mediated immunity plays a fundamental role in control of intestinal nematode infection. Here we report a different impact of Foxp3(+) regulatory T cells (Treg) in nematode-induced evasion of IL-9-mediated immunity in BALB/c and C57BL/6 mice. Infection with Strongyloides ratti induced Treg expansion with similar kinetics and phenotype in both strains. Strikingly, Treg depletion reduced parasite burden selectively in BALB/c but not in C57BL/6 mice. Treg function was apparent in both strains as Treg depletion increased nematode-specific humoral and cellular Th2 response in BALB/c and C57BL/6 mice to the same extent. Improved resistance in Treg-depleted BALB/c mice was accompanied by increased production of IL-9 and accelerated degranulation of mast cells. In contrast, IL-9 production was not significantly elevated and kinetics of mast cell degranulation were unaffected by Treg depletion in C57BL/6 mice. By in vivo neutralization, we demonstrate that increased IL-9 production during the first days of infection caused accelerated mast cell degranulation and rapid expulsion of S. ratti adults from the small intestine of Treg-depleted BALB/c mice. In genetically mast cell-deficient (Cpa3-Cre) BALB/c mice, Treg depletion still resulted in increased IL-9 production but resistance to S. ratti infection was lost, suggesting that IL-9-driven mast cell activation mediated accelerated expulsion of S. ratti in Treg-depleted BALB/c mice. This IL-9-driven mast cell degranulation is a central mechanism of S. ratti expulsion in both, BALB/c and C57BL/6 mice, because IL-9 injection reduced and IL-9 neutralization increased parasite burden in the presence of Treg in both strains. Therefore our results suggest that Foxp3(+) Treg suppress sufficient IL-9 production for subsequent mast cell degranulation during S. ratti infection in a non-redundant manner in BALB/c mice, whereas additional regulatory pathways are functional in Treg-depleted C57BL/6 mice. Author Summary Parasitic worms are large multicellular organisms that manage completion of their life cycles despite exposure to their host's immune system. To avoid expulsion, parasitic worms actively suppress their host's immune response. Here we show that the pathogenic nematode Strongyloides ratti induces the expansion of a specialized subset of regulatory immune cells, regulatory T cells (Treg), that counteract effector T cell function. Treg expanded with similar kinetics and suppressed most features of the nematode-specific immune response in two different mouse strains, BALB/c and C57BL/6. One central factor of this immune response i.e. IL-9-driven rapid degranulation of mast cells, was suppressed by parasite-induced Treg in BALB/c mice non-redundantly. Consequently, Treg depletion elevated IL-9 production, accelerated mast cell degranulation and led to rapid expulsion of S. ratti in BALB/c mice. S. ratti-infected C57BL/6 mice still displayed low IL-9 production and delayed mast cell degranulation in the absence of Treg. Thus S. ratti was able to complete its life cycle in Treg-depleted C57BL/6 mice. This study shows that parasitic worms delay their expulsion by over-activating regulatory elements of their host's immune system such as Treg. The importance of individual regulatory elements during immune evasion depends on their degree of redundancy within the host that is variable in different genetic backgrounds.