The skin is the largest organ of the human body and functions as a physical and immunologic barrier against external pathogens and chemical and physical assaults. Adaptive immune responses against microorganisms and autoantigens in various inflammatory dermatoses are largely mediated by circulating and skin-resident T cells.¹ In fact, the skin is the largest tissue reservoir of T cells. The cutaneous surface of a normal adult contains approximately 20 billion antigen-experienced memory T cells that provide cutaneous immunosurveillance, nearly twice the number present in the entire circulation.² In this chapter, we will discuss the various T-cell effector subtypes and their distinct transcriptional regulatory programs, cytokine expression patterns, and roles in cutaneous inflammatory and infectious processes. In addition, we will highlight their potential contribution to cutaneous lymphomagenesis (Figs. 1-1 and 1-2).

T cells recognize their specific antigens through interaction between the membrane-bound T-cell receptors (TCRs) and the antigen-major histocompatibility complex (MHC) presented by the antigen-presenting cells (APCs). A TCR consists of a heterodimer composed of either α and β or γ and δ chains. The TCR chains undergo random genetic recombination steps to encode unique antigen receptors that recognize an infinitely diverse group of antigens present on bacteria, viruses, parasites, and tumor cells. The αβ- or γδ-lineage commitment occurs very early during T-cell differentiation. Expression of the transcription factor SOX13 by triple-negative (TN2) (CD3⁻CD4⁻CD8⁻) thymocytes inhibits the Wnt/T-cell factor (TCF) pathway and promotes γδ T-cell development, while unopposed Wnt/TCF activity leads to αβ T-cell differentiation.³ The TCR is closely associated with the pan–T-cell marker CD3, which is essential in signal transduction initiated by TCR–antigen interaction.^4,5

T cells can be divided into two subgroups on the basis of their expression of CD4 or CD8 membrane coreceptors. CD4⁺ T cells recognize protein antigen bound to class II MHC molecules on APCs and mainly function as helper cells, whereas CD8⁺ T cells recognize protein antigen bound to class I MHC on target cells and mainly function as cytotoxic cells.^6,7

In skin infections, APCs, including Langerhans cells (LCs) in the epidermis and myeloid-derived dendritic cells (DCs) in the dermis, phagocytose invading pathogens and migrate to skin-draining secondary lymphoid organs (SLOs). Within the SLO (i.e., lymph node and lymphoid follicles), LCs/DCs migrate into the T-cell–rich paracortex through CCR7-CCL19/21-dependent chemotaxis, allowing for MHC–TCR conjugation and antigen-specific activation of naïve and memory CD4⁺ helper and CD8⁺ cytotoxic T cells.^{8,9,10,11,12,13,14} Activated T cells upregulate skin-homing chemokine receptors CCR4 and CCR10, which promote their exit into the circulation.^15,16,17,18 In addition, the same chemokine receptors upregulate T-cell cutaneous lymphocyte antigen (CLA), which targets T-cell adhesion and extravasation into the skin by binding to E- and P-selectins on cutaneous endothelial cells.^{10,18,19,20,21,22,23} The final extravasation of T cells to the skin requires firm attachment to the endothelium through interactions between T-cell integrin leukocyte function antigen (LFA-1) and intercellular/vascular cell adhesion molecules (ICAM/VCAM) expressed on the endothelium. The expression of ICAM and VCAM can be induced by proinflammatory cytokines such as TNF-α, IFN-γ, and IL-1 secreted at the site of infection.^22,24 Once extravasated, T cells utilize additional integrins to transmigrate through the dermal extracellular matrix. A minority of T cells further migrate to the epidermis. However, the mechanisms of T cell localizing to particular layers of the epidermis have not been fully elucidated.²²

Differentiation of CD4⁺ T cells into specific T helper phenotypes is highly dependent on the antigen presented by APCs as well as the cytokine/chemokine microenvironment at the time of activation.²⁵ In the steady-state skin, approximately 80% of T cells have an αβ⁺, CD4⁺ phenotype. Most (>85%) of these cells are T helper 1 (T_H1) cells as defined by their capability to secrete cytokines such as IFN-γ and IL-2. A minority of skin-resident T cells have an IL-4-producing T_H2 or IL-10/TGF-β-producing immunosuppressive regulatory T (T_reg) cell phenotype.^2,26,27 In addition, on the basis of the preferential expression of IL-17, IL-22, IL-9, and CXCL-13, recent studies have identified novel subtypes of T helper cells, including T_H17, T_H22, T_H9, and follicular T helper (T_FH) cells, respectively.^28,29,30,31 These T cells are generally not present in steady-state skin, but may be recruited during inflammation. The relevance of these CD4⁺ T-cell subsets in pathogen eradication, skin homeostasis, inflammatory dermatoses, and cutaneous T-cell lymphomas (CTCLs) will be discussed in more detail in the following sections.