Gamma Delta T Cells and Their Pathogenic Role in Psoriasis

Abstract

γδT cells are an unconventional population of T lymphocytes that play an indispensable role in host defense, immune surveillance, and homeostasis of the immune system. They display unique developmental, distributional, and functional patterns and rapidly respond to various insults and contribute to diverse diseases. Although γδT cells make up only a small portion of the total T cell pool, emerging evidence suggest that aberrantly activated γδT cells may play a role in the pathogenesis of psoriasis. Dermal γδT cells are the major IL-17-producing cells in the skin that respond to IL-23 stimulation. Furthermore, γδT cells exhibit memory-cell-like characteristics that mediate repeated episodes of psoriatic inflammation. This review discusses the differentiation, development, distribution, and biological function of γδT cells and the mechanisms by which they contribute to psoriasis. Potential therapeutic approaches targeting these cells in psoriasis have also been detailed.

Keywords: IL-17; biological function; psoriasis; skin inflammation; γδT.

Figure 1

Schematic depicting the development of γδ and αβ T cells in the thymus. γδ and αβ cells develop from the same ancestral DN (CD4-CD8-) cells. Lineage changes in γδ and αβ cells mainly occur at the DN3 stage. Cell surface markers and transcription factors of the cells have been labeled alongside.

Figure 2

Role of γδT cells in the immune pathogenesis of psoriasis. Keratinocytes in the epidermis undergo apoptosis, necrosis, or death when exposed to certain external stimulation. With the release of cell contents, such as DNA and RNA, keratinocytes release antimicrobial peptides, such as LL-37. LL-37 binds with DNA and RNA to form a complex, promote immature DC activation, and secrete IFN-γ/IL-23 through the TLR7/8/9 pathway. IL-23 activates RORγt+γδT cells to secrete IL-17. γδT cell-derived IL-17 directly inhibits IGF-1 production in DETCs by increasing epidermal IL-23/IL-1β expression. During excessive keratinocyte proliferation, the secretion of TNF-α and chemokine ligand 20 (CCL20) increases, which consequently recruits CCR6+γδT cells to the inflammatory site of the epidermis. IL-17 cytokines produced by γδT cells potently upregulate the chemokine, CCL20, in keratinocytes, which chemoattracts IL-17A-producing CCR6+ immune cells to the inflamed site, thus forming a positive feedback loop. Il-23/IL-17 also promotes the recruitment of neutrophils to inflammatory sites, leading to excessive proliferation of the stratum corneum to form psoriatic inflammatory lesions. γδT cells have memory properties and can migrate rapidly to inflammatory sites through the blood and skin when subjected to a secondary stimulation. This consequently gives rise to severe inflammatory manifestations.