AUTHOR=Tokura Yoshiki , Phadungsaksawasdi Pawit , Kurihara Kazuo , Fujiyama Toshiharu , Honda Tetsuya TITLE=Pathophysiology of Skin Resident Memory T Cells JOURNAL=Frontiers in Immunology VOLUME=11 YEAR=2021 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.618897 DOI=10.3389/fimmu.2020.618897 ISSN=1664-3224 ABSTRACT=

Tissue resident memory T (T_RM) cells reside in peripheral, non-lymphoid tissues such as the skin, where they act as alarm-sensor cells or cytotoxic cells. Physiologically, skin T_RM cells persist for a long term and can be reactivated upon reinfection with the same antigen, thus serving as peripheral sentinels in the immune surveillance network. CD8⁺CD69⁺CD103⁺ T_RM cells are the well-characterized subtype that develops in the epidermis. The local mediators such as interleukin (IL)-15 and transforming growth factor (TGF)-β are required for the formation of long-lived T_RM cell population in skin. Skin T_RM cells engage virus-infected cells, proliferate in situ in response to local antigens and do not migrate out of the epidermis. Secondary T_RM cell populations are derived from pre-existing T_RM cells and newly recruited T_RM precursors from the circulation. In addition to microbial pathogens, topical application of chemical allergen to skin causes delayed-type hypersensitivity and amplifies the number of antigen-specific CD8⁺ T_RM cells at challenged site. Skin T_RM cells are also involved in the pathological conditions, including vitiligo, psoriasis, fixed drug eruption and cutaneous T-cell lymphoma (CTCL). The functions of these T_RM cells seem to be different, depending on each pathology. Psoriasis plaques are seen in a recurrent manner especially at the originally affected sites. Upon stimulation of the skin of psoriasis patients, the CD8⁺CD103⁺CD49a^- T_RM cells in the epidermis seem to be reactivated and initiate IL-17A production. Meanwhile, autoreactive CD8⁺CD103⁺CD49a⁺ T_RM cells secreting interferon-γ are present in lesional vitiligo skin. Fixed drug eruption is another disease where skin T_RM cells evoke its characteristic clinical appearance upon administration of a causative drug. Intraepidermal CD8⁺ T_RM cells with an effector-memory phenotype resident in the skin lesions of fixed drug eruption play a major contributing role in the development of localized tissue damage. CTCL develops primarily in the skin by a clonal expansion of a transformed T_RM cells. CD8⁺ CTCL with the pagetoid epidermotropic histology is considered to originate from epidermal CD8⁺ T_RM cells. This review will discuss the current understanding of skin T_RM biology and their contribution to skin homeostasis and diseases.