Pathophysiology of Skin Resident Memory T Cells

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.

Keywords: cutaneous T cell lymphoma; fixed drug eruption; psoriasis; resident memory T cell; skin; skin immunity; vitiligo.

Figure 1

Characterization of skin resident memory T cell.

Figure 2

Adhesion of T_RM cell in the skin.

Figure 3

Development of skin T_RM cell.

Figure 4

Maintenance of skin T_RM cell.

Figure 5

Mechanism of psoriasis.

Figure 6

Double immunofluorescent staining. Left: CD4 (red) and CD103 (green). Right: CD8 (red) and CD103 (green). Merged yellow color (right) indicate cells positive for both CD8 and CD103, representing T_RM cells.

Figure 7

Mechanism of vitiligo.

Figure 8

Histopathology (left; hematoxylin and eosin, HE) and immunostaining for CD4 (middle) and CD8 (right) in CD8⁺ pagetoid reticulosis.

Figure 9

Mechanism of fixed drug eruption.