Cutting edge: Extrinsic and intrinsic sex effects differentially regulate pulmonary ILC2 numbers, phenotype, and function.

Pulmonary type 2 innate lymphocytes (ILC2s) show sex dimorphism in numbers, phenotype, and function. We used a novel strategy of competitive, mixed male-female donor bone marrow chimeras to determine if sex differences in murine ILC2s result from extrinsic factors in the recipient environment or from durable intrinsic variables in donor cells. We show that the recipient sex environment regulated ILC2 numbers and IL33R/ST2 and KLRG1 surface levels, independent of donor sex. In contrast, ILC2 production of interleukin (IL)-5 depended on donor cell sex and the type of inflammatory stimulus. After allergen exposure, or upon treatment of naïve lung cells with PMA/ionomycin, a higher frequency of female donor-derived ILC2s produced IL-5. In contrast, influenza virus infection induced a greater proportion of male donor-derived ILC2s to produce IL-5. Thus, while a current sex environment governed pulmonary ILC2 numbers and canonical markers, ILC2 functional responses were shaped by durable factors stemming from intrinsic biological sex.