Age-dependent rise in IFN-γ competence undermines effective type 2 responses to nematode infection

Abstract

The efficient induction of type 2 immune responses is central to the control of helminth infections. Previous studies demonstrated that strong Th1 responses driven by intracellular pathogens as well as a bias for type 1 activity in senescent mice impedes the generation of Th2 responses and the control of intestinal nematode infections. Here, we show that the spontaneous differentiation of Th1 cells and their expansion with age restrains type 2 immunity to infection with the small intestinal nematode H. polygyrus much earlier in life than previously anticipated. This includes the more extensive induction of IFN-γ competent, nematode-specific Th2/1 hybrid cells in BALB/c mice older than three months compared to younger animals. In C57BL/6 mice, Th1 cells accumulate more rapidly at steady state, translating to elevated Th2/1 differentiation and poor control of parasite fitness in primary infections experienced at a young age. Blocking of early IFN-γ and IL-12 signals during the first week of nematode infection leads to sharply decreased Th2/1 differentiation and promotes resistance in both mouse lines. Together, these data suggest that IFN-γ competent, type 1 like effector cells spontaneously accumulating in the vertebrate host progressively curtail the effectiveness of anti-nematode type 2 responses with rising host age.

Ascaris suum infection in juvenile pigs elicits a local Th2 response in a setting of ongoing Th1 expansion

“…Conversely, enforced type 1 signaling via IL-12/IFN-g resulted in the delayed control of infections (26). Similarly, our group has shown that the age-dependent increase in IFN-g competence interferes with the formation of an effective type 2 response in H. polygyrus infected mice, resulting in impaired parasite control at an advanced age (27). Moreover, laboratory mice that were transferred from pathogen-free to outdoor environments lost the ability to develop sterile immunity against the nematode T. muris, which was associated with an immune response shifted towards Th1 and thus increased susceptibility (28).…”

“…However, the significance of local vs. systemic immune responses in controlling tissue-migrating nematodes remains unclear. Laboratory mice infected with rodent nematodes, such as H. polygyrus, often mount both strong systemic and local Th2 responses (27,63). They develop long-lasting and stable Th2 memory populations (64), and are effectively protected against challenge infections (35).…”

“…Another factor promoting Th1 development and IFN-g availability is immune maturation and aging. Our group recently showed that the increase of IFN-g levels observed in matured mice altered the fitness of H. polygyrus (27). Furthermore, it has been shown that Trichuris-specific IFN-g production increased with age, suggesting that the phenotype of the protective immune response against the helminth might be altered depending on host age (86).…”