NK cells promote Th-17 mediated corneal barrier disruption in dry eye

Background: The conjunctiva contains a specialized population of lymphocytes that reside in the epithelium, named intraepithelial lymphocytes (IEL). Methodology/Principal Findings: Here we characterized the IEL population prior to and after experimental desiccating stress (DS) for 5 or 10 days (DS5, DS10) and evaluated the effect of NK depletion on DS. The frequency of IELs in normal murine conjunctiva was CD3⁺CD103⁺ (~22%), CD3⁺γδ⁺ (~9.6%), CD3⁺NK⁺ (2%), CD3^-NK⁺ (~4.4%), CD3⁺CD8α (~0.9%), and CD4 (~0.6%). Systemic depletion of NK cells prior and during DS led to a decrease in the frequency of total and activated DCs, a decrease in T helper-17⁺ cells in the cervical lymph nodes and generation of less pathogenic CD4⁺T cells. B6.nude recipient mice of adoptively transferred CD4⁺T cells isolated from NK-depleted DS5 donor mice showed significantly less corneal barrier disruption, lower levels of IL-17A, CCL20 and MMP-3 in the cornea epithelia compared to recipients of control CD4⁺T cells. Conclusions/Significance: Taken together, these results show that the NK IELs are involved in the acute immune response to desiccation-induced dry eye by activating DC, which in turn coordinate generation of the pathogenic Th-17 response.