Immune competent mice eject the Strongyloides ratti after one month. Still, S. ratti is a successful parasite, as this limited time span is fully sufficient to reproduce, complete its life cycle and propagate its genes. To ensure survival for this one month, S. ratti, like most helminths, actively suppresses the immune response that is directed towards itself. We have shown that immune evasion is conveyed, among other pathways, by the expansion of Foxp3+ regulatory T lymphocytes (Treg) that antagonize IL-9 production and subsequent IL-9-mediated mast cell activation (Blankenhaus 2014 and 2011). This pathway was dominant in BALB/c mice where Treg depletion accelerated mast cell activation and reduced intestinal parasite burden. Interestingly, additional layers of regulation occurred in C57BL/6 mice that displayed a similar expansion of Treg but remained susceptible for S. ratti after Treg depletion. Next to Tregs that remain the primary regulatory pathway for maintaining peripheral tolerance, a complex network of co-inhibitory receptors acts as a second fine-tuning level of regulation. Infection with S. ratti increased expression of several co-inhibitory receptors on T cells in BALB/c and C57BL/6 mice. Of note, this induction was more pronounced in C57BL/6 mice (Hartmann 2021). Focusing on the co-inhibitory receptor B and T lymphocyte Attenuator (BTLA), we reported that either deficiency for BTLA or its ligand HVEM promoted the mast cell and IL-9-mediated anti-S. ratti immunity in C57BL/6 mice (Breloer 2015).  Currently we investigate the impact of the addtional HVEM ligands LIGHT and CD160 in regulating anti-S. ratti immunity.

Analysing the impact of helminth-induced immunomodulation on the immune response to third party antigens we observed reduced antibody responses to model antigen immunization in mice with pre-existing L. sigmodontis infection (Hartmann 2011,  2012 and 2015; Haben 2014). Extending this observation to a clinically relevant system, we report that L. sigmodontis-infected mice that were vaccinated against seasonal influenza, using licensed human vaccines, displayed suppressed antibody responses. Protection against subsequent challenge infections with the human pathogenic 2009 pandemic H1N1 influenza A virus (swine flu) was also impaired (Hartmann 2019). Interestingly, vaccination efficacy was impaired in mice that were vaccinated during acute L. sigmodontis infection, but also in mice that were vaccinated after immune-driven resolution of L. sigmodontis infection. The suppressed status of acutely and formerly L. sigmodontis-infected mice was correlated to a sustained and systemic expansion of CD4⁺CD49⁺LAG3⁺IL-10⁺ Tr1 cells and partially abrogated by IL-10 receptor neutralization. Neither repeated vaccinations nor introduction of mild adjuvants, that were licensed for humans, restored vaccination efficacy in L. sigmodontis-infected mice (Hartmann 2022). Also drug-induced deworming did not restore the responsiveness to a vaccination given 2 weeks after treatment, as Tr1 frequencies were still high although all worms were killed at the time point of vaccination. Only a combination of deworming and improved vaccination regimen restored vaccination-induced protection against an influenza challenge infection in formerly helminth-infected mice (Stetter 2021), reviewed in (Breloer 2023).