Origin of type 2 innate lymphoid cells in the skin

Type 2 innate lymphoid cells (ILC2s) are a recently discovered subset of immune cells that have been found to be an important source of the cytokines that characterize parasitic infections and allergic immune responses. Accordingly, ILC2s have been shown to contribute to the immune response in mouse models of allergy and atopic dermatitis, but the details of where and when ILC2s originate are poorly understood. To determine the proportion of skin ILC2s that are locally derived, we surgically joined pairs of congenically distinct mice so as to allow sharing of blood circulation. Results from these parabiosis experiments were consistent with tissue residency and limited circulation of skin ILC2s. To determine the origin of adult skin ILC2s, we used a lineage-tracing strategy using two independent strains of tamoxifen-inducible Cre mice to mark the progeny of cells based on the timing of tamoxifen administration. Results from prenatal administration of tamoxifen showed that while a small fraction of adult skin ILC2s are embryonically derived, the majority of skin ILC2s are derived postnatally. Results from postnatal administration of tamoxifen showed a significantly higher fraction of lineage-traced ILC2s, but in contrast to other tissues in which the ILC2 pool is relatively stable throughout adulthood, skin ILC2s were replaced by de novo ILC2s at a faster rate, perhaps reflecting responses to inflammatory signals from from microbial or environmental stimuli. The origin of ILC2s has implications for the timing of therapies targeting these cells, and further work will be necessary to determine factors contributing to the turnover of these potent mediators of type 2 immune responses.