The Biological Basis of Disease Recurrence in Psoriasis

A Historical Perspective and Current Models

Lluís Puig; Antonio Costanzo; Ernesto J. Muñoz-Elías; Maria Jazra; Sven Wegner; Carle F. Paul; Curdin Conrad


The British Journal of Dermatology. 2022;186(5):773-781. 

In This Article

Tissue-resident Memory T Cells and Psoriasis Immunopathology

A detailed review on the pathophysiology of TRM cells was recently published;[53] 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.[57] 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.[58] 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[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.[59] 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.[60] The most notable biological characteristics of TRM cells are their longevity and low migration rates away from their resident tissue.[60] 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.[64]

In 2017, Cheuk et al.[65] differentiated CD49+CD8+ TRM cells from CD49CD8+ 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.[66]

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.[67]