The hygiene hypothesis is the leading concept to explain the current asthma epidemic, which is built on the observation that a lack of bacterial contact early in life induces allergic T_H2 immune responses.

Because little is known about the contribution of respiratory tract viruses in this context, we evaluated the effect of prior influenza infection on the development of allergic asthma.

Mice were infected with influenza and, once recovered, subjected to an ovalbumin- or house dust mite–induced experimental asthma protocol. Influenza-polarized effector memory T (Tem) cells were transferred adoptively to allergen-sensitized animals before allergen challenge. A comprehensive in silico analysis assessed homologies between virus- and allergen-derived proteins. Influenza-polarized Tem cells were stimulated ex vivo with candidate peptides. Mice were immunized with a pool of virus-derived T-cell epitopes.

In 2 murine models we found a long-lasting preventive effect against experimental asthma features. Protection could be attributed about equally to CD4⁺ and CD8⁺ Tem cells from influenza-infected mice. An in silico bioinformatic analysis identified 4 influenza- and 3 allergen-derived MHC class I and MHC class II candidate T-cell epitopes with potential antigen-specific cross-reactivity between influenza and allergens. Lymphocytes from influenza-infected mice produced IFN-γ and IL-2 but not IL-5 on stimulation with the aforementioned peptides. Immunization with a mixture of the influenza peptides conferred asthma protection, and peptide-immunized mice transferred protection through CD4⁺ and CD8⁺ Tem cells.

For the first time, our results illustrate heterologous immunity of virus-infected animals toward allergens. This finding extends the original hygiene hypothesis.