Qian-Nan Xu and Hai-Qin Zhu*

Department of Dermatology,Shanghai Ruijin Hospital North,Shanghai 201801,China.

Introduction

Tissue-resident memory T(TRM)cells are a subset of recently identified noncirculating memory T cells characterized by long-term persistence in nonlymphoid peripheral tissues such as the skin,gut,lung,kidney,and reproductive tract[1].The skin is the largest organ in the human body,and estimated 2×1010T cells are present in the entire skin surface.Most of these are CD45RO+memory T cells that express the skinhoming addressins cutaneous leukocyte antigen(CLA)and chemokine receptor(CCR)4[2].Recent studies have indicated that these abundant resident T cells within skin,especially the skin TRM cells,play important roles in the pathogenesis of dermatoses,including psoriasis and atopic dermatitis(AD).Unlike the well-characterized circulating central memory T cells and effector memory T cells,TRM cells persist in the skin and do not recirculate into the blood[3].

The major capacity of TRM cells in skin is to survive and stay poised in the skin for active engagement in pathogen clearance and immune alerting.Huge amounts of microbes reside on the skin surface and in subepidermal areas,and common cutaneous diseases such as AD and psoriasis are strongly associated with the skin microbiome.As a quick response to invading microbes,skin TRM cells contribute in different ways in various dermatoses.Researchers have shown that mice kept in clean,pathogen-free barrier facilities have few skin TRM cells,possibly because these cells are generated by the infections that barrier facilities are designed to prevent[4].When the skin is infected by herpes simplex virus or vaccinia virus,populations of skin CD8+T cells motivated to resolve the acute infection,and remained in the skin to provide rapid clearance of viral reinfection[5].In several dermatoses,such as psoriasis,pathogenic autoreactive TRM cells induce fixed and recurrent skin lesions,and TRM cells specific for environmental allergens could worsen allergic asthma and contact dermatitis.In this review,we introduce the immue features and functions of skin TRM cells,and summary the advance of skin TRM cells in some dermatoses.

Immune features and functions of skin TRM cells

Immune features of skin TRM cells

T cells remain in the circulation until they are recruited to the skin upon the development of inflammation.Few T cells are present in non-inflamed skin.After clearance of an infection,the recruited T cells either exit the skin or undergo apoptosis.In a study as early as 2001,however,a group of CD8+T cells remained in virus-infected tissue for the long term[6],and a subsequent study showed that antigenspecific CD8+T cells migrated to non-lymphoid tissues and resided as long-lived memory cells following infection[7].A study in 2004 showed that immunodeficient mice on which non-lesional skin of patients with psoriasis had been grafted grew lesional skin more rapidly than immunodeficient mice,on which skin from normal healthy people had been grafted.This indicated that a population of resident pathogenic T cells were present in the non-lesional skin of psoriasis patients[8].It was subsequently demonstrated that all human skin T cells were CD45RO+memory T cells that coexpressed the skin homing addressins CLA and CCR4[9-11]and that all of them were also αβT cells.These cells do not express CCR7 or CD62L because they do not enter the blood circulation or lymph nodes.Skin-resident T cells remain in the skin independent of antigen stimulation.A small portion of skin-resident T cells are CD8+TRM cells,which are located in the baseline membrane of the epidermis and the junction between the epidermis and dermis.These CD8+T cells highly express CD103,and their proliferation is limited.Most skin-resident T cells are CD4+cells,located near the vessels in the dermis,do not express CD103,and have high proliferative ability[12-13].

Immune functions of skin TRM cells

Approximately 98%of skin-tropic memory T cells are located in skin under non-inflamed conditions,and only 2%are located in the circulation[9].These cells are unique because they are not recruited from the peripheral blood during infection,allowing them to act promptly when the skin barrier is challenged by various factors that may violate the balanced environment of the skin.Na?ve T cells degenerate into effector memory T cells and central memory T cells,while a portion of them highly express skin-homing receptors such as cutaneous lymphocyte antigen,CCR4,CCR10,and other receptors[11].Thus,these cells are recruited to the skin and remain as long-term residents.When the skin encounters the same antigen again,the TRM cells in skin can trigger the immune response and clear the infection without the presence of antibodies or circulating T cells[14-15].Through secretion of interferon-γ(IFN-γ),interleukin(IL)-2,IL-4,IL-17,and IL-22,skin-resident T cells play multiple roles in various skin diseases[14,16].

Roles of skin TRM cells in dermatoses

Skin TRM cells in psoriasis

A study in 2002 demonstrated that blockade of E-selectin(meaning that the T cells in blood could not migrate to the skin)was not related to reduced recurrence of psoriatic skin.This finding indicates that skin TRM cells are involved in the pathogenesis of psoriasis[17]. Moreover, experiments showed that psoriatic lesions developed when non-lesional,normalappearing skin of patients with psoriasis was grafted onto immunodeficient mice[8].In another research,a specific group of CD8+T cells remained activity in previously psoriatic lesions[18].A further study indicated that IL-22-secreting CD4+T cells and IL-17-secreting CD8+T cells,which were residents in psoriatic skin,contributed to the exaggeration of lesional skin[19]and that these cells were CD49a-negative CD8+T cells[20].Other work showed that resident IL-17-producing αβ T-cell clones with psoriasis-specific antigen receptors were detected in clinically resolved psoriatic skin lesions[21]and that these cells likely represent the disease-initiating pathogenic T cells in psoriasis that are correlated with early relapse following ultraviolet B phototherapy[22].The above mentioned studies definitively demonstrate that TRM cells in both psoriatic lesions and non-lesional skin play a role the pathogenic pathway of psoriasis.

Skin TRM cells in vitiligo

Multiple combinatorial factors are involved in the progress of vitiligo,with the immune system,particularly T cells,playing a prominent role.After repigmentation,vitiligo frequently recurs in the same area,suggesting that vitiligo may involve the presence of TRM cells.Studies have indicated that stable and active perilesional skin in patients with vitiligo is enriched with CD8 TRM cells expressing CD69 and CD103 compared with psoriasis-affected and unaffected(control)skin[23].CD8 TRM cells that express CD103 are localized mainly in the epidermis.Expression of CXC chemokine receptor 3 is observed on most CD8+TRM cells,including melanocytespecific CD8 T cells,in patients with vitiligo[24].CD8 TRM cells show increased production of tumor necrosis factor-α and IFN-γ with moderate cytotoxic activity.The presence of functional CD8 TRM cells in both stable and active patients with vitiligo,reinforcing the concept of vitiligo as an immune memory skin disease.The CD8 TRM cells that remain in stable disease stage could play a role during disease flares,emphasizing the interest in targeting such a cell subset in patients with vitiligo.Furthermore,these TRM cells may be related to the recurrence of vitiligo due to interaction with the microbial community of the skin[25].

Skin TRM cells in AD

AD is featured by robust immune activation.Various T-cell subsets,including Th2/Th22 cells,are added in lesional and non-lesional skin.TRM cells were proved to contribute to the recurrence of AD.While greater T-cell infiltrates were found in lesional than non-lesional skin of AD,diversity of the T-cell receptor repertoire was similar in lesional and non-lesional skin,and the absolute number of unique T-cell clones was correlated with respective T-cell counts.Most(87%)top expanded T-cell clones in lesional tissues were shared with non-lesional tissues,and they were largely main-tained after 4 monthes of successful treatment of topical triamcinolone[26].Additionally,Staphylococcus aureusandStaphylococcusspeciesin the skin microbiota trigger AD through TRM cells[27].Furthermore,ultraviolet radiation as a treatment of AD may also alleviate the disease by affecting the skin TRM cells[2],which may due to metabolic reprogramming and longevity of TRM cells[28].

Skin TRM cells in mycosis fungoides

Mycosis fungoides(MF)is characterized by malignant T cells that are observed only in well-demarcated fixed inflammatory lesions.Although The MF lesions may appear to be resolved with topical steroid therapy,they loften persist for decades and usually recur in the same location once therapy is discontinued.Malignant T cells in patients with MF lack expression of L-selectin and CCR7 and phenotypically resemble TRM cells,and are consistent with their tendency to form fixed inflammatory lesions[29].One study indicated that the failure of treatment to achieve prolonged clinical remission may be related to the activation of TRM cells in skin[30].

Skin TRM cells in fixed drug eruption

Fixed drug eruption is a distinct variant of druginduced dermatoses featured by their relapse in the same location after administration of the causative drug.Because of the TRM cells in the lesions,activation of these cells can rapidly produce large amounts of IFN-γ epsilon followed by localized epidermal injury[31].CD8+TRM cells are recognized as playing an important role in the recurrent site-specific inflammation in patients with fixed drug eruption[32].Stable populations of T cells that constitutively express T-cell receptor-αβ,CD45RA,CD103,CLA,CD11b,and CD69 but not CD27 or CD56 can be recognized in lesional skin of patients with fixed drug eruption[33].These TRM cells,which are enriched in resting lesions of fixed drug eruption,could have originally evolved to protect the integrity of the epidermal tissue from invading pathogens such as herpes viruses.Once the drug antigen is crossrecognized by the T cells,they can be activated to kill surrounding keratinocytes,consequently resulting in localized epidermal damage.

Conclusions and perspectives

Skin TRM cells are strongly associated with various skin diseases as evidenced by their roles in the recurrence and remission of the lesional skin in psoriasis,vitiligo,MF,AD,and fixed drug eruption.However,the potential roles of TRM cells in other skin diseases such as pemphigus or systemic lupus erythematosus,which also have a high risk of relapse,remain unknown.Could TRM cells also contribute to the development of these skin diseases?Moreover,skin TRM cell activation is seemingly closely related to skin microbes;therefore,could controlling the skin microenvironment serve as another way to treat the above-mentioned skin diseases?Finally,the specific functions of TRM cells in psoriasis,vitiligo,MF,AD,and fixed drug eruption are still unclear.Determination of the unique roles of skin TRM cells in these skin diseases may promote the development of new treatments as depletion and local control of skin TRM cells decreases the recurrence of these diseases.