Graduate Student University of Iowa Iowa City, Iowa, United States
Disclosure(s):
Maddison Lensing: No financial relationships to disclose
Introduction/Rationale: Alopecia Areata (AA) is a prevalent autoimmune disease affecting 2% of the population and presents as nonscarring hair loss. In AA, CD8 T Cells have been found infiltrating around and within the hair follicle and are identified as main drivers of disease. Our transcriptional analysis has revealed that CD8 T cells in the skin of AA patients are poised to make effector molecules such as interferon gamma (IFNg), perforin, and granzymes. Similarly, in the C3H/HeJ murine model of AA, pathogenic NKG2D+ CD8 T cells expressed more IFNg, perforin, and Granzyme B than non-pathogenic T cells. Given the close spatial relationship between CD8 T cells and the hair follicle end target, our objective was to assess the contributions of CD8 T cell-derived molecules during disease.
Methods: We assessed the role of CD8 T cell molecules in a C3H/HeJ murine model of AA, wherein pathogenic CD8 T cells are sorted from the skin draining lymph nodes of AA mice, expanded in vitro, and intradermally injected into naïve recipients. We used RosaERTcreIFNgKO or RosaERTcrePrfKO mice, capable of tamoxifen-inducible global knockdown of IFNg or Perforin, as donors. Mice globally deficient in the IFNg-receptor(IFNgrKO), bone marrow chimeras with an IFNgrKO hematopoietic compartment, or WT mice were used as recipients.
Results: We observed perforin deficient CD8 T cells were capable of transferring disease in a manner comparable to WT cells. Conversely, IFNg deficient CD8 T cells failed to transfer disease. Furthermore, global IFNgrKO mice were incapable of developing AA following CD8 T cell induction and bone marrow chimeras containing an IFNgrKO hematopoietic compartment were also unable to develop disease.
Conclusion: Overall, our findings suggest that perforin is dispensable, while IFNg is a crucial pathogenic effector molecule employed by CD8 T cells in AA. Sensing of IFNg by the immune compartment was a vital step of disease pathogenesis, and future studies may decipher how IFNg sensing by the hair follicle impacts disease.
