Recently, long-lived TRM cells have been identified in peripheral tissues, especially the skin (reviewed in [32]). TRM cells do not recirculate as compared to TEM and TCM cells. While the characterization of TRM cells is still in its infancy in humans, mouse studies have recently

X-396 cost shed more light on this novel T-cell population, which is best characterized in the CD8+ T-cell compartment. This is due to the preferential use of viral infection models such as models for herpes simplex and human immunodeficiency virus infections and the fact that tissue-resident memory T cells are located in the epidermal skin layer, which in mice is exclusively populated by CD8+ but not CD4+ T cells (reviewed in [33]). In humans, however, CD4+ T cells can reside in the epidermis. Therefore, it can be anticipated that insights gained in mouse models will only reflect the situation

in humans with some limitations. Nevertheless, mouse models have so far been crucial for providing evidence of fundamental principles, such as the concept INCB024360 of tissue residency versus tissue recirculation, due to the fact that it is possible to easily perturb the immune system by infections and parabiosis, as well as by virtual unrestricted tissue accessibility for further analysis. A prerequisite for defining the specific role(s) for Th-cell subsets in tissue is to define how they reach their target organ. In line with a specific chemokine repertoire, distinct Th-cell subsets show characteristic homing abilities. Important chemokine receptors for skin homing are CLA, CCR4, CCR6, and CCR10 (reviewed in [34]). The chemokine receptor CCR10 has been shown to be

abundantly present on Th22 cells [5] and reflects PJ34 HCl a characteristic feature of these cells, namely migration to higher layers of the epithelium according to a CCL27 gradient [35]. In line with this observation, Th22 cells are present in inflammatory skin diseases and predominantly found in the epidermal compartment [4]. This holds also true for other immune cells. For example, Th17 cells induce keratinocytes to secrete CXCL8, which in turn recruits neutrophilic granulocytes into the epidermis and drives the development of neutrophil microabscesses, a hallmark of psoriasis [36]. Thus, not only the differential expression of chemokine receptors but also the chemokine repertoire that distinct Th cells induce in the tissue are critical for their functional abilities. This can have a critical impact on the pathogenesis of tissue-restricted diseases. Once Th cells reach their target organ, a T-cell activation cascade is necessary to fully activate them. This may happen in different ways.