Role of IFN-y in the immunity and control of gastrointestinal nematode infections

Infections by gastrointestinal nematodes mandate an effective type 2 response for the parasite clearance. In line with the cross-regulatory nature of Th1 lineage specifying factors on the differentiation of Th2 cells seen at the molecular level, strong type 1 activity resulted by inflammation associated with senescence, specific genetic predisposition and co-infections with intracellular pathogens exacerbate the Th2 responses resulting in poor resistance in nematode infections. Despite reported cross-regulation, the Th1 and Th2 pathways are not mutually exclusive as polarization with IFN-g, IL-12 and IL-4 results in the generation of T-bet and GATA-3 co-expressing Th2/1 cells in vitro. Th2/1 cells are also induced naturally in nematode infections (Affinass et al., 2018; Bock et al., 2017; Peine et al., 2013).
In the current study we demonstrate that the IFN-g competence progressively rises with the age of uninfected BALB/c mice displaying high resistance to nematode infection. The elevated type 1 bias in 5-10 months old compared to 2-3 months old mice resulted in poor parasite control manifested by higher female fecundity in the mature cohort infected with H. polygyrus. The poor resistance was accompanied by stronger generation and mucosal accumulation of Th2/1 hybrid cells and elevated proportions of parasite specific IFN-g producing cells.
Substantiating the above findings, restriction of IFN-g availability in the priming phase of nematode infection led to improved resistance coinciding with sharp reduction in systemic and mucosal Th2/1 cells and a near complete absence of parasite specific IFN-g producing cells. Conversely, supplementation of early IFN-g availability led to impaired parasite control associated with robust expansion of Th2/1 cells and a significant rise in IFN-g producing cells in parasite specific T cell pool. Importantly, elevated IFN-g availability did not inhibit classical Th2 cells in the long run and rather promoted an accumulation of systemic GATA-3+ Teff cells in IFN-g treated BALB/c mice. The increased parasite egg production upon IFN-g treatment was traced back to the increased fitness of the L4 larvae maturating in the gut of IFN-g treated mice.
In line with the findings in differently aged mice, C57BL/6 mice genetically predisposed to higher susceptibility in H. polygyrus infection more rapidly accumulate Th1 cells at steady state compared to resistant BALB/c mice. The elevated type 1 activity in C57BL/6 mice translated to greater accumulation of small intestinal Th2/1 cells post infection and poor resistance compared to BALB/c mice. However, the stark differences seen between the strains at younger age leveled out in older mice due to increased IFN-g competence and increased bias in favor of Th2/1 cells in mature BALB/c mice. Restricting IFN-g availability in C57BL/6 mice led to increased resistance thereby substantiating the significance of IFN-g in differential susceptibility across inbred lines. Overall, our findings report an age-dependent reduction in anti-nematode type 2 immunity resulted by steady state accumulation of IFN-g competent effector cells in the vertebrate host.