P5 - Impact of age-dependent IFN-g competence on immunity to Ascaris infection
Graphical abstract of project P5
Image Credit: Institute of Immunology
Resistance to Ascaris infection depends on CD4+GATA-3+ Th2 cells producing the cytokines IL-4, -5 and -13. Conversely, T-bet+Th1 cells and other cell types can severely impair Th2 differentiation in experimental coinfections with Toxoplasma or Plasmodium (1,2). Importantly, IFN-γ-competent CD4+ Th1 cells generated independently of infection are already present in neonates. We showed, that these memory-phenotype (MP) Th1 cells expand rapidly after birth and join with infection-driven, newly generated Th1 cells in the defense against intracellular pathogens later in life (3,4). However, in the context of nematode infections, our recent work showed that high numbers of IFN-γ-competent MP-Th1 cells accumulating along the transition of mice from juvenile to fully mature state impede efficient pathogen control (3,4). Our group further showed that a natural Th2 bias in the mucosa of neonatal pigs converts into a Th1-biased environment within a few weeks after birth (5) and pigs infected with A. suum after weaning develop strong systemic Th1 along with modest Th2 cell responses (6).
Therefore, this project aims to decipher the impact of age-dependent IFN-γ-competence in human and porcine Ascaris infections. Two projects will test the overarching question if an age-dependent rise of IL-12 tips the scales by relegating ambiguous IL18/-33 signaling (capable of supporting Th2 and Th1 cells) to the joint support of IFN-γ release from expanded MP-Th1 cells. We will thereby clarify if an IL-12/IFN-γ bias developing early after birth in humans and pigs impedes the generation of efficient Th2 in favor of Th1 and Th2/1 hybrid responses in humans and pigs, potentially resulting in frequent reinfections, delayed decline of infection intensities and in marked impact on human and animal health.
References:
1) Ahmed et al. 2017, doi: 10.3389/fcimb.2017.00341; 2) Coomes et al. 2015, doi: 10.1371/journal.ppat.1004994; 3) Affinass et al. 2018, doi: 10.1002/eji.201847639; 4) Kapse et al. 2022, doi: 10.1038/s41385-022-00519-6; 5) Schlosser-Brandenburg et al. 2021, doi: 10.3389/fimmu.2021.734153; 6) Oser et al. 2024, doi: 10.3389/fimmu.2024.1396446.