Nippostrongylus brasiliensis, a rodent model of hookworm infection, is known to induce strong Th2 differentiation of CD4 T cells. A recently discovered subset of innate cells, the Type 2 innate lymphoid cells (ILC2s), have been shown to produce cytokines traditionally attributed to Th2 cells. During a primary infection ILC2s contribute to expulsion of the hookworms from the intestines, but previous work from our lab has shown that Th2 responses in the lung are responsible for protection against secondary infection.
We hypothesised that ILC2s may be contributing to lung immunity against hookworm infection. We began by showing that ILC2s greatly increase in number in response to a primary Nippostrongylus brasiliensis infection. Using interleukin 4 (IL-4)/IL-13 dual reporter mice we observed that these cells are activated as measured by increased expression of the IL-13 reporter. Secondary infection increased further the number of IL-13 reporting ILC2s and these increases correlated with less larvae surviving in the lungs, which we define as protection. Both IL-4 and IL-13 signal through STAT6 and while this transcription factor is required for protection, we found IL-4 is dispensable indicating IL-13 is sufficient to drive protective responses. CD4 depletion prior to secondary infection leads to loss of protection and diminished ILC2 responses. Investigating a role for CD4 T cell derived cytokines in the activation of ILC2s revealed that treatment with IL-2 complex was able to restore both protection and ILC2 numbers in the absence of CD4 T cells.
In summary we have shown for the first time the contribution of lung ILC2s to the protective immunity against reinfection by Nippostrongylus brasiliensis, and elucidated potential mechanisms via which CD4 T cells augment the activation of this population.