Resident memory T cells in dirty mice suppress innate cell activation and infiltration into the skin following stimulation with alarmins

Trm cells are sequestered at barrier tissues as a swift first line defense against peripheral reinfections in both antigen dependent and antigen independent bystander modes. Trm cells are also capable of mediating autoimmune diseases, such as psoriasis, wherein autoreactive Trm cells are aberrantly activated. To quickly combat infections, activated Trm cells can stimulate the influx and activation of memory T cells and innate immune cells. However, there is significant heterogeneity in the inflammatory responses that Trm cell populations can induce, specifically in the activation of the innate profile. Most studies to date have utilized a reductionist approach to examine single Trm populations, specific pathogens, and defined tissues. Herein, we adopted a more holistic approach utilizing barrier-free ‘dirty’ mice to profile activated innate cells attracted to the skin in the presence of quiescent cutaneous Trm cells. Notably, dirty mice are a more human predictive model due to having a diverse microbial experience that leads to the development of a complete complement of Trm cells in the skin. We demonstrate that in the dirty mouse model mice have a significant reduction in cutaneous neutrophils and monocytes compared to SPF mice following local treatment with two separate innate stimuli. These findings reveal that cutaneous Trm cells have the capacity to temper the innate immune response and further substantiate the implication that Trm cells are heterogenous in their functions depending in large part on their tissue residency. However, in an autoimmune microenvironment Trm cells are capable of recruiting innate cells to the site of an exposure to a damage-associated molecular pattern. Likely due to the imbalance of IL-17 and IFN-γ.