γδT-cells are unconventional T lymphocytes that are only sparsely found in blood and secondary lymphoid organs. Instead, they are enriched in barrier organs such as the skin and can respond to conserved self and non-self antigens to assist in tissue immunosurveillance. Today, it is well accepted that γδT-cells, which express pro-inflammatory cytokines such as IL-17, IL-22, and IFN-γ, are associated with the pathogenesis of skin-related autoimmune diseases such as psoriasis and alopecia.
How and which antigens are sensed by γδT-cells and how this promotes autoimmune phenomena is still a topic of active debate. However, one prominent role of γδT-cells is the recognition and response towards host-derived molecules up-regulated by cellular stress. In the study, the authors opted to try and understand if γδT-cells, by acting as stress-sentinels in the vicinity of the hair follicle (HF), can be responsible for initiating a pro-inflammatory response towards “stressed” HFs.
It is known that the microdissection procedure and collapse of tissue perfusion followed by transfer into an in vitro culture environment stress the cells that make up the HF. Under physiological circumstances, HFs enjoy a status of immune privilege (IP). However, freshly cultured HFs transiently down-regulate the expression of key IP molecules and up-regulate a myriad of stress-related molecules that can activate γδT-cells, until they finally adapt to tissue culture conditions. Armed with this knowledge, the authors took advantage of this “acute stress” and co-cultured freshly isolated HFs with γδT-cells. They observed that γδT-cells migrate towards those stressed HFs and are rendered cytotoxic, mediating the collapse of the HF IP and also premature catagen, two hallmarks of alopecia areata.
In addition to revealing this key aspect of γδT-cell and HF biology and how it relates to the human disease alopecia areata, the authors show that human HF cultures can be an invaluable tool for translational research. In the field of γδT-cell biomedical research, the more traditional mouse models have several disadvantages that may compromise the translatability of the results: namely, there is a significant lack of conservation between human and mouse γδT-cell ontogeny, diversity, functionality, and frequency.
Therefore, by establishing an ex vivo culture system in which the interaction of human γδT-cells with freshly isolated HFs can be probed, the method reported by the researchers can now be applied by other researchers in their research. As such, both the results and the novel human ex vivo model reported will contribute to a better understanding of the pathogenesis of γδT-cell-mediated autoimmune diseases such as alopecia areata and psoriasis.
Reference:
Youhei Uchida, Jennifer Gherardini, Karin Pappelbaum, Jérémy Chéret, Andreas Schulte-Mecklenbeck, Catharina C Gross, Natasa Strbo, Amos Gilhar, Alfredo Rossi, Wolfgang Funk, Takuro Kanekura, Luís Almeida, Marta Bertolini, Ralf Paus
‘Resident human dermal γδT-cells operate as stress-sentinels: Lessons from the hair follicle’
J Autoimmun. 2021 Aug 31;124:102711. doi: 10.1016/j.jaut.2021.102711
