Bhavya Kapse (Berlin / DE), Joshua Adjah (Berlin / DE), Hongwei Zhang (Berlin / DE), Univ.-Prof. Dr. rer. nat. Susanne Hartmann (Berlin / DE), Dr. Sebastian Rausch (Berlin / DE)
Abstract text
Protective type-2 immunity against helminth infection is impaired in experimental systems biased for the production of the type-1 cytokine IFN-γ. Upon birth, Th1-like memory phenotype (MP) cells generated in the absence of infection rapidly expand and accumulate over time. We hence asked whether a rise of IFN-γ competence along host age affects the development of protective type-2 responses in mice infected with the small intestinal nematode H. polygyrus.
Th1 cells expanded significantly in lymphoid and mucosal tissue with host age in uninfected BALB/c mice. Consequently, BALB/c mice infected at the age of 3-9 months displayed more extensive induction of IFN-γ competent, nematode-specific Th2/1 hybrid cells compared to younger animals. In more susceptible C57BL/6 mice, Th1 cells accumulated 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 IFN-γ and IL-12 signals during the first week of nematode infection leads to sharply decreased Th2/1 differentiation and promoted resistance in both mouse lines, whereas young BALB/c mice treated with IFN-γ at the onset of infection mirrored the Th2/1 hybrid-biased responses of older BALB/c as well as young C57BL/6 mice.
Together, these data show that the spontaneous accumulation of IFN-γ competent, type 1 like effector cells progressively curtails the effectiveness of anti-nematode type 2 responses with rising host age. However, elevated IFN-γ signaling early during nematode infection strongly promotes the differentiation and systemic accumulation of GATA-3+T-bet+ Th2/1 hybrid cells rather than restraining the GATA-3+ effector T cell response. In part, more extensive systemic responses in IFN-γ-rich environments could be explained by impaired colonization of effector cells in the gut alongside the restricted expansion of Foxp3+ T cells.