Tissue-resident Memory T Cells and Psoriasis Immunopathology
A detailed review on the pathophysiology of TRM cells was recently published; here we focus on specific aspects of TRM cells as they relate to psoriasis. In the 1990s, published evidence supported the concept of a role for skin-homing T cells in the pathogenesis of inflammatory skin disease, by trafficking from the blood into lesional skin via the vascular addressin E-selectin.[54–56] However, in 2002 Bhushan et al. reported that an anti-E-selectin monoclonal antibody (CDP850) was ineffective in treating chronic plaque psoriasis, and suggested the alternative hypothesis that skin-resident T cells are critical for psoriasis development. Subsequently, supporting evidence from the immunodeficient AGR129 mouse model showed that skin-resident T cells in human skin grafts undergo local proliferation and infiltration of the host dermis and epidermis. The T-cell infiltrate triggered an inflammatory cascade and expression of a psoriatic phenotype in the host. The cytokine TNF-α was shown to be a key regulator of local T-cell proliferation and disease development.
In 2006, a key study showed that there are 2 × 10 T cells (predominantly Th1 memory effector cells) in healthy human skin (dermis and epidermis), nearly twice as many as those circulating in the blood. These results suggested the existence of a large pool of TRM cells in healthy skin that can initiate and perpetuate immune responses in the absence of T-cell recruitment from the blood.
TRM cells residing in epithelial barrier tissues in the gastrointestinal, respiratory and reproductive tracts, and skin, provide a rapid adaptive defence against pathogens. The most notable biological characteristics of TRM cells are their longevity and low migration rates away from their resident tissue. TRM cells can be divided into CD8+ and CD4+ subsets. CD8+ TRM cells are localized in the epidermis where they play a critical role in immune responses; CD4+ TRM cells are less well characterized and potentially play a critical role in protective immunity against bacterial and fungal infections in the skin.[60,61] The majority of CD8+ TRM cells express the cell marker CD103 (also known as integrin alpha-E), which is implicated in lodging TRM cells in the epidermis[62,63] via binding of the T cells to E-cadherin, a highly expressed epithelial protein.
In 2017, Cheuk et al. differentiated CD49+CD8+ TRM cells from CD49–CD8+ TRM cells. CD49+ TRM cells are characterized by IFN-γ production and rapidly gain a cytotoxic capacity following IL-15 stimulation, whereas CD49– TRM cells produce IL-17. The functional dichotomy between CD49+ and CD49– TRM cells was evident in a comparison of TRM cell characteristics in two distinct immune-mediated skin diseases. In vitiligo skin, where melanocytes are locally eradicated by cytotoxic activity, skin biopsy specimens showed a predominance of cytotoxic CD49+ TRM cells, compared with skin biopsy specimens from psoriatic lesions, which contained predominantly IL-17-producing CD49– TRM cells. In summary, the data from this study showed that CD49 expression delineated CD8+ TRM cell specialization in human skin.
Recently, Vo et al. reported that CD8+ TRM cells were enriched in both psoriatic lesional and non-lesional skin compared with normal skin. Furthermore, the percentage ratio of IL-17A-producing cells to IFN-γ-producing cells in the whole CD8 fraction correlated with disease duration.
Casciano et al. identified an increased population of circulating CD8+ central memory T (TCM) cells with a CCR4+CXCR3+ phenotype in isolated peripheral blood mononuclear cells from patients with psoriasis compared with healthy controls. This implicates the skin as a key trafficking site for TCM cells, where antigen encounter may occur and, under appropriate conditions, may lead to the generation of non-circulating TRM cells. The authors suggest that CCR4+CXCR3+ T cells could represent a key population of TCM cells that play a role in disease recurrence or redistribution to distant sites such as joint synovial tissues and entheses.
The British Journal of Dermatology. 2022;186(5):773-781. © 2022 Blackwell Publishing