Innate Lymphocytes in Psoriasis

Abstract

Skin is a fundamental component of our host defense system that provides a dynamic physical and chemical barrier against pathogen invasion and environmental insults. Cutaneous barrier function is mediated by complex interactions between structural cells such as keratinocytes and diverse lineages of immune cells. In contrast to the protective role of these intercellular interactions, uncontrolled immune activation can lead to keratinocyte dysfunction and psoriasis, a chronic inflammatory disease affecting 2% of the global population. Despite some differences between human and murine skin, animal models of psoriasiform inflammation have greatly informed clinical approaches to disease. These studies have helped to identify the interleukin (IL)-23-IL-17 axis as a central cytokine network that drives disease. In addition, they have led to the recent description of long-lived, skin-resident innate lymphocyte and lymphoid cells that accumulate in psoriatic lesions. Although not completely defined, these populations have both overlapping and unique functions compared to antigen-restricted αβ T lymphocytes, the latter of which are well-known to contribute to disease pathogenesis. In this review, we describe the diversity of innate lymphocytes and lymphoid cells found in mammalian skin with a special focus on αβ T cells, Natural Killer T cells and Innate Lymphoid cells. In addition, we discuss the effector functions of these unique leukocyte subsets and how each may contribute to different stages of psoriasis. A more complete understanding of these cell types that bridge the innate and adaptive immune system will hopefully lead to more targeted therapies that mitigate or prevent disease progression.

Keywords: disease; innate; lymphocyte; psoriasis; skin.

Figure 1

γδ T cells and ILCs in psoriatic skin. Diverse subsets of γδ T cells colonize the skin. Under homeostatic conditions, the mouse epidermis contains dendritic epidermal T cells, which are a monoclonal population of Vγ5⁺ cells. The dermis contains Vγ4⁺ and Vγ6⁺ γδ T cells enriched for expression of IL-23R, CCR6, and IL-7R. In mouse models of psoriasiform inflammation, activated keratinocytes produce chemokines such as CCL2 and CCL20, which subsequently recruit dermal γδ T cells to the epidermis. Among these γδ T cells, there is a subgroup that express the transcriptional factor RORγt, that are capable of producing IL-17 and IL22 upon IL-1 and IL-23 stimulation. Both mouse and human studies have shown that, upon cytokine stimulation, dermal-derived γδ T cells secrete IL-17 and IL-22 that drives keratinocyte hyperplasia, neutrophil recruitment and disease progression. ILCs are also present in the healthy skin. They are divided into three groups based on transcription factor expression and effector functions. Under steady-state conditions, ILC2 are the largest population. ILC3 are currently thought to be the dominant population that contribute to disease progression. In human skin lesions, NKp44⁺ ILC3s are able to produce IL-22 and IL-17 that exacerbate disease progression.

Figure 2

NK and NKT cells in psoriatic skin. NK and NKT cells are innate immune cells that have cytokine-producing and cytotoxic functions. They both reside in the dermis. The NK cells can be divided into two groups, namely cNK and trNK cells, based on the receptors CD49a and DX5. Unlike NK cells, NKT cells also express an antigen-specific TCR that recognizes glycolipid through CD1 presentation by antigen-presenting cells. In psoriatic skin lesions, NK and NKT cells are rare. However, CD1d expression is reported to be elevated in keratinocytes in inflamed skin. In addition, NK and NKT cells have decreased degranulation ability, but display increased IFNγ production. High IFNγ production can contribute to an increase in keratinocyte-derived chemokines such as CXCL10 and CCL5, and the elevated expression of MHCI, both of which increase cell recruitment and presentation of autoantigens. In addition, NK and NKT cells produce TNFα that activate keratinocytes in an IL-24/Stat3-dependent manner as well as indirectly enhance dermal IL-17⁺T cell activation by facilitating dendritic cells to produce IL-1 and IL-23.